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ID PMID Title PublicationDate abstract
26718436 Association between functional CD24 polymorphisms and susceptibility to autoimmune disease 2015 Dec 26 This study aimed to explore whether the functional CD24 A57V and TG/del polymorphisms are associated with susceptibility to autoimmune diseases. A meta-analysis was conducted on the associations between the CD24 A57V and TG/del polymorphisms and autoimmune diseases using (1) allele contrast, and (2) the recessive, (3) dominant, and (4) co-dominant models. Twenty-six comparative studies with 7,507 patients and 8,803 controls were included in the meta-analysis. The meta-analysis revealed a significant association between autoimmune disease and the CD24 Val allele (OR = 1.285, 95% CI = 1.177-1.403, p = 1.0 × 10-9). Meta-analysis by autoimmune disease type showed a significant association between the CD24 Val allele and multiple sclerosis (MS) (OR = 1.420, 95% CI = 1.239-1.628, p = 4.7 × 10-8) and systemic lupus erythematous (SLE) (OR = 1.282, 95% CI = 1.081-1.521, p = 0.004), but not Crohn's disease (CD) (OR = 1.003, 95% CI = 0.826-1.218, p = 0.974). Meta-analysis of the CD24 Val/Val genotype showed an association with ulcerative colitis (OR = 1.778, 95% CI = 1.148-2.753, p = 0.010). In addition, meta-analysis by autoimmune disease type revealed a significant association between the CD24 TG-deletion allele and MS (OR = 0.596, 95% CI = 0.415-0.856, p = 0.005) and CD (OR = 1.594, 95% CI = 1.175-2.161, p = 0.003). This meta-analysis indicates that the functional CD24 A57V and TG/del polymorphisms are associated with susceptibility to multiple autoimmune diseases including SLE, MS, UC and CD.
26841119 Serum Calprotectin Versus Acute-Phase Reactants in the Discrimination of Inflammatory Dise 2016 Jul OBJECTIVE: To compare the accuracy of serum calprotectin and acute-phase reactants (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) in stratifying disease activity in rheumatoid arthritis (RA) patients receiving tumor necrosis factor inhibitors (TNFi), and to correlate calprotectin levels with TNFi trough serum levels. METHODS: We conducted a cross-sectional study of 87 RA patients receiving adalimumab, etanercept (ETN), or infliximab (IFX); 56 psoriatic arthritis (PsA) patients and 40 healthy blood donors were included as controls. Associations between calprotectin, CRP, and ESR and composite articular indices (Disease Activity Score in 28 joints [DAS28], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index) were analyzed by correlation and linear regression and the accuracy and discriminatory capacity of calprotectin by receiver operator characteristic curves (area under the curve [AUC]). RESULTS: Calprotectin levels correlated better with all composite activity indices than CRP and ESR (all r coefficients >0.70). Calprotectin levels were significantly lower in RA and PsA patients in clinical remission compared with those with low disease activity for all articular indices. In RA, ESR discriminated between remission and low disease activity only when using DAS28, and CRP only with SDAI. In RA patients in remission/low disease activity, calprotectin but not CRP or ESR distinguished between patients with no swollen joints and those with ≥1 swollen joint (1.74 μg/ml versus 3.04 μg/ml; P = 0.010). Using DAS28 ≥2.6 as the reference variable, calprotectin showed an AUC of 0.92; the best cutoff was ≥2.47 μg/ml with a likelihood ratio of 6.3 (95% confidence interval 2.5-15.8). Calprotectin serum levels inversely correlated with trough serum drug levels of ETN (ρ = -0.671, P < 0.001) and IFX (ρ = -0.729, P = 0.017). CONCLUSION: Calprotectin may more accurately discriminate disease activity in RA patients receiving TNFi than acute-phase reactants, even in patients with low inflammatory activity.
27864565 Targeting non-canonical nuclear factor-κB signalling attenuates neovascularization in a n 2017 Feb OBJECTIVE: Angiogenesis is crucial in RA disease progression. Lymphotoxin β receptor (LTβR)-induced activation of the non-canonical nuclear factor-κB (NF-κB) pathway via NF-κB-inducing kinase (NIK) has been implicated in this process. Consequently, inhibition of this pathway may hold therapeutic potential in RA. We describe a novel three-dimensional (3D) model of synovial angiogenesis incorporating endothelial cells (ECs), RA fibroblast-like synoviocytes (RAFLSs) and RA synovial fluid (RASF) to further investigate the contributions of NF-κB in this process. METHODS: Spheroids consisting of RAFLSs and ECs were stimulated with RASF, the LTβR ligands LTβ and LIGHT, or growth factor bFGF and VEGF, followed by quantification of EC sprouting using confocal microscopy and digital image analysis. Next, the effects of anginex, NIK-targeting siRNA (siNIK), LTβR-Ig fusion protein (baminercept) and a novel pharmacological NIK inhibitor were investigated. RESULTS: RASF significantly promoted sprout formation, which was blocked by the established angiogenesis inhibitor anginex (P < 0.05). LTβ and LIGHT induced significant sprouting (P < 0.05), as did bFGF/VEGF (P < 0.01). siNIK pre-treatment of ECs led to reductions in LTβR-induced vessel formation (P < 0.05). LTβR-Ig not only blocked LTβ- or LIGHT-induced sprouting, but also RASF-induced sprouting (P < 0.05). The NIK inhibitor blocked angiogenesis induced by LTβ, LIGHT, growth factors (P < 0.05) and RASF (P < 0.01). CONCLUSION: We present a novel 3D model of synovial angiogenesis incorporating RAFLSs, ECs and RASF that mimics the in vivo situation. Using this system, we demonstrate that non-canonical NF-κB signalling promotes neovascularization and show that this model is useful for dissecting relative contributions of signalling pathways in specific cell types to angiogenic responses and for testing pharmacological inhibitors of angiogenesis.
25964493 Immune tolerance induction with multiepitope peptide derived from citrullinated autoantige 2015 Jun 15 Citrullinated peptides are major targets of disease-specific autoantibodies in rheumatoid arthritis. Currently, citrullinated peptides are used as biomarkers for diagnosing rheumatoid arthritis by measuring anti-citrullinated protein Ab (ACPA) titers in patients' sera. The accumulation of citrullinated proteins at synovial inflammation sites suggests that they are possible targets for tolerance induction. The objective of the present study was to determine whether citrullinated peptides could induce tolerance in an experimental arthritis model in rats. In view of the multiplicity of target citrullinated autoantigens described for ACPA, we generated a multiepitope citrullinated peptide (Cit-ME), derived from major prevalent citrullinated autoantigens (citrullinated filaggrin, fibrinogen, vimentin, and collagen type II), and studied its effects on arthritic rats. Adjuvant-induced arthritis was induced in Lewis rats. Beginning at day 7 after disease induction, the rats received eight s.c. injections of Cit-ME on alternate days. Differences in clinical status and modulation of T cell populations were analyzed. In adjuvant-induced arthritis rats treated with Cit-ME, disease severity was significantly reduced compared with that of untreated rats. Moreover, amelioration of disease manifestations was related to an increased regulatory T cell subset and an elevated apoptosis rate of T cells associated with reduced Th17 cells. Thus, the use of citrullinated peptides-based immunotherapy may be a promising approach for tolerance induction in experimental arthritis and perhaps even in susceptible individuals that are ACPA-seropositive in human arthritis.
25539428 Frequency of radiologic procedures in patients with rheumatoid arthritis. 2015 Jan BACKGROUND: Patients with rheumatoid arthritis (RA) undergo radiologic investigations for disease and comorbidity evaluation. The actual use of radiologic imaging in RA is unknown. METHODS: Using the Rochester Epidemiology Project medical record linkage system, adult patients from previously assembled population-based cohorts of Olmsted County, Minnesota, residents who fulfilled the 1987 American College of Rheumatology criteria for RA in 1988 to 2007 and comparator subjects without RA of similar age and gender were studied. Data on all radiologic procedures performed were collected. RESULTS: The study included 650 patients with RA and 650 patients without RA. Patients with RA had significantly more radiographs of the chest (rate ratio [RR], 1.33; 95% confidence interval [CI], 1.28-31.38), upper extremity (RR, 2.97; 95% CI, 2.80-83.17), lower extremity (RR, 2.05; 95% CI, 1.94-102.16), spine (RR, 1.46; 95% CI, 1.35-41.59), and hip, pelvis, or sacroiliac joints (RR, 1.14; 95% CI, 1.03-11.26), as well as bone radionuclide (RR, 1.90; 95% CI, 1.50-52.44) and dual-energy x-ray absorptiometry imaging (RR, 1.77; 95% CI, 1.59-61.98) compared with patients without RA. Among patients with RA, having a positive rheumatoid factor was associated with an increased likelihood of undergoing radiologic procedures (RR, 1.05; 95% CI, 1.02-11.07). Women with RA underwent more imaging procedures than men (RR, 1.20; 95% CI, 1.16-21.23). CONCLUSIONS: Patients with RA undergo more radiologic procedures than patients without RA. Among patients with RA, women and patients with a positive rheumatoid factor have more radiologic procedures. The utilization of radiography is likely a reflection of overall disease burden. Despite some guidelines, routine hand wrist radiographs were not obtained with regularity; "overuse" is unlikely.
26635183 Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patien 2016 Jul OBJECTIVE: To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA). METHODS: Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations. RESULTS: Overall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept. CONCLUSIONS: Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.
26710104 Construct Validation of a Multidimensional Computerized Adaptive Test for Fatigue in Rheum 2015 OBJECTIVE: Multidimensional computerized adaptive testing enables precise measurements of patient-reported outcomes at an individual level across different dimensions. This study examined the construct validity of a multidimensional computerized adaptive test (CAT) for fatigue in rheumatoid arthritis (RA). METHODS: The 'CAT Fatigue RA' was constructed based on a previously calibrated item bank. It contains 196 items and three dimensions: 'severity', 'impact' and 'variability' of fatigue. The CAT was administered to 166 patients with RA. They also completed a traditional, multidimensional fatigue questionnaire (BRAF-MDQ) and the SF-36 in order to examine the CAT's construct validity. A priori criterion for construct validity was that 75% of the correlations between the CAT dimensions and the subscales of the other questionnaires were as expected. Furthermore, comprehensive use of the item bank, measurement precision and score distribution were investigated. RESULTS: The a priori criterion for construct validity was supported for two of the three CAT dimensions (severity and impact but not for variability). For severity and impact, 87% of the correlations with the subscales of the well-established questionnaires were as expected but for variability, 53% of the hypothesised relations were found. Eighty-nine percent of the items were selected between one and 137 times for CAT administrations. Measurement precision was excellent for the severity and impact dimensions, with more than 90% of the CAT administrations reaching a standard error below 0.32. The variability dimension showed good measurement precision with 90% of the CAT administrations reaching a standard error below 0.44. No floor- or ceiling-effects were found for the three dimensions. CONCLUSION: The CAT Fatigue RA showed good construct validity and excellent measurement precision on the dimensions severity and impact. The dimension variability had less ideal measurement characteristics, pointing to the need to recalibrate the CAT item bank with a two-dimensional model, solely consisting of severity and impact.
27431352 Sjögren Syndrome: Why Do Clinical Trials Fail? 2016 Aug Sjögren syndrome (SS) comprises glandular and extraglandular manifestations. Double-blind prospective trials of traditional disease-modifying antirheumatic drugs and biologics have failed because they have not improved benign symptoms, the major cause of lowered quality of life. Rituximab has proven effective in SS patients with associated mixed cryoglobulinemia, parotid gland swelling, lymphocytic interstitial pneumonitis, thrombocytopenia, and other manifestations. There were few of these SS patients in the trials required for FDA approval. Most patients had benign symptoms and did not show benefit, leading to failure of the study. This article examines the reasons for these failures and proposes future directions.
27869736 Circulating IL-27 Is Elevated in Rheumatoid Arthritis Patients. 2016 Nov 18 Cytokines are key immunoregulatory molecules that regulate T lymphocyte-mediated immune responses and inflammatory reactions. We determined whether there is aberrant expression of interleukin-27 (IL-27) in rheumatoid arthritis (RA) patients and investigated the clinical significance of these changes. IL-27 is a key cellular factor that regulates the differentiation of CD4+ T cells, which can secrete interleukin-10 (IL-10) and interleukin-17 (IL-17) in vivo. Concentrations of serum IL-27 in 67 RA patients, and 36 sex- and age-matched control subjects were measured by enzyme-linked immunosorbent assay (ELISA). Results showed that concentrations of serum IL-27 in all RA patients were significantly higher than in healthy control subjects, and there was a significant and positive correlation between serum IL-27 levels and disease activity in all RA patients. Levels of serum IL-27 in RA patients were significantly correlated with disease activity score in 28 joints (DAS28). Moreover, immunosuppressive treatment with leflunomide downregulated the levels of IL-27 in active RA patients. Therefore, the elevated production of circulating T cell inflammatory factors contributes to the pathogenesis of RA, and serum IL-27 could potentially serve as a new biomarker of RA disease activity.
26943656 Characterization and Localization of Citrullinated Proteoglycan Aggrecan in Human Articula 2016 BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease of the synovial joints. The autoimmune character of RA is underscored by prominent production of autoantibodies such as those against IgG (rheumatoid factor), and a broad array of joint tissue-specific and other endogenous citrullinated proteins. Anti-citrullinated protein antibodies (ACPA) can be detected in the sera and synovial fluids of RA patients and ACPA seropositivity is one of the diagnostic criteria of RA. Studies have demonstrated that RA T cells respond to citrullinated peptides (epitopes) of proteoglycan (PG) aggrecan, which is one of the most abundant macromolecules of articular cartilage. However, it is not known if the PG molecule is citrullinated in vivo in human cartilage, and if so, whether citrulline-containing neoepitopes of PG (CitPG) can contribute to autoimmunity in RA. METHODS: CitPG was detected in human cartilage extracts using ACPA+ RA sera in dot blot and Western blot. Citrullination status of in vitro citrullinated recombinant G1 domain of human PG (rhG1) was confirmed by antibody-based and chemical methods, and potential sites of citrullination in rhG1 were explored by molecular modeling. CitPG-specific serum autoantibodies were quantified by enzyme-linked immunosorbent assays, and CitPG was localized in osteoarthritic (OA) and RA cartilage using immunohistochemistry. FINDINGS: Sera from ACPA+ RA patients reacted with PG purified from normal human cartilage specimens. PG fragments (mainly those containing the G1 domain) from OA or RA cartilage extracts were recognized by ACPA+ sera but not by serum from ACPA- individuals. ACPA+ sera also reacted with in vitro citrullinated rhG1 and G3 domain-containing fragment(s) of PG. Molecular modeling suggested multiple sites of potential citrullination within the G1 domain. The immunohistochemical localization of CitPG was different in OA and RA cartilage. CONCLUSIONS: CitPG is a new member of citrullinated proteins identified in human joints. CitPG could be found in both normal and diseased cartilage specimens. Antibodies against CitPG may trigger or augment arthritis by forming immune complexes with this autoantigen in the joints of ACPA+ RA patients.
27384545 Understanding the Regulatory Roles of Natural Killer T Cells in Rheumatoid Arthritis: T He 2016 Oct Rheumatoid arthritis (RA) is the most common chronic systemic autoimmune disease. This disease is thought to be caused by pathogenic T cells. Th1, Th2, Th17 and Treg cells have been implicated in the pathogenesis of RA. These Th cells differentiate from CD4+ T cells primarily due to the effects of cytokines. Natural killer T (NKT) cells are a distinct subset of lymphocytes that can rapidly secrete massive amount of cytokines, including IL-2, IL-4, IL-12 and IFN-γ. Numerous studies showed that NKT cells can influence the differentiation of CD4+ T cells via cytokines in vitro. These findings suggest that NKT cells play an important role in RA by polarizing Th1, Th2, Th17 and Treg cells. In view of the complexity of RA, we discussed whether NKT cells really influence the development of RA through regulating the differentiation of Th cells.
27553253 Are online symptoms checkers useful for patients with inflammatory arthritis? 2016 Aug 24 BACKGROUND: Online symptom checkers are increasingly used by patients however there is little published evidence of their effectiveness in real patients. The aim of this study was to evaluate how patients with inflammatory arthritis and inflammatory arthralgia use the internet to look for health information and to assess the advice given and diagnoses suggested by the NHS and WebMD symptom checkers in relation to the patients' actual diagnoses. METHODS: Thirty-four patients with inflammatory arthritis (rheumatoid arthritis (n = 13), psoriatic arthritis (n = 4), unclassified arthritis (n = 4)) and inflammatory arthralgia (n = 13) newly presenting to a secondary care based clinic were identified using a consecutive sampling approach. Consenting patients were asked questions about their internet use in relation to their presenting symptoms. They then completed the NHS and the WebMD symptom checkers and their answers and the outcomes were recorded. RESULTS: Sixteen patients had previously consulted the internet regarding their symptoms. Neither age nor gender significantly influenced internet usage. Actions advised via the NHS symptom checker were: call an ambulance (n = 11), attend A&E (n = 4), contact your GP straight away (n = 2), see your GP today (n = 6), or see your GP within 36 h (n = 11). The 5 most common differential diagnoses given by Web MD were gout (n = 28), rheumatoid arthritis (n = 24), psoriatic arthritis (n = 22), osteoarthritis (n = 18) and finger dislocation (n = 10). The most common first differential diagnosis was osteoarthritis (n = 12). Only 4 out of 21 patients with inflammatory arthritis were given a first diagnosis of rheumatoid arthritis or psoriatic arthritis. CONCLUSIONS: Our data highlight that help seeking advice given online is often inappropriate and that the diagnoses suggested are frequently inaccurate. Recommendations to seek emergency advice may cause inappropriate healthcare utilization.
27018050 Methotrexate-associated orbital lymphoproliferative disorder in a patient with rheumatoid 2016 May PURPOSE: Lymphoproliferative disorders (LPDs) can develop in patients treated with methotrexate (MTX) and usually respond well to MTX withdrawal. Mucosa-associated lymphoid tissue (MALT) lymphoma is a relatively rare type of MTX-LPD. The development of MTX-LPD in the orbit has not been previously described. We here report a case of orbital MALT lymphoma that disappeared after MTX withdrawal in a patient treated with MTX for rheumatoid arthritis. CASE: A 78-year-old woman who complained of swelling of the left upper eyelid had been treated with MTX for >8 years for rheumatoid arthritis. Slit-lamp examination revealed a temporal subconjunctival mass, salmon pink in color, in the left eye. Fundus photographs also suggested the presence of a temporal tumor in the left orbit. [(18)F]Fluorodeoxyglucose positron emission tomography-computed tomography revealed highly integrated lesions in the left inferotemporal orbit and a left external iliac lymph node, a left obturator lymph node, and an inguinal lymph node. Pathologic analysis of a tumor biopsy specimen showed small- and medium-sized lymphocytes positive for CD20, MIB-1, and bcl-2 and negative for CD10, CD3, bcl-1, IgG4, and EBV-ISH. On the basis of these findings, we diagnosed the tumor as MTX-induced MALT lymphoma. The subconjunctival and orbital masses disappeared gradually over 10 months after MTX withdrawal and did not recur within 2 years. CONCLUSION: This case of orbital MTX-LPD suggests that the possibility of MTX-LPD should be considered even for ocular tumors in patients treated with MTX.
25739993 Surface or full cementation of the tibial component in total knee arthroplasty: a matched- 2015 May INTRODUCTION: Despite the clinical success of cemented TKA, aseptic loosening of the tibial component remains a potential long-term complication. Considering the constantly growing revision burden, there is a need for clarification regarding controversial views on primary fixation techniques. In this retrospective analysis, surface (SC) or full cementation (FC) of tibial components was compared in a matched-pair and long-term setting. METHODS: Matching pairs were identified in a patient series from 1989 to 1994. Hence, 25 primary TKA (SC) were compared to 42 TKA (FC). The study population included 34 patients with rheumatoid arthritis. Patients were matched in a 1:1.7 fashion according to age, gender and initial diagnosis. Outcome was assessed by multiple clinical parameters, detailed radiographic evaluation and survivorship analysis. RESULTS: Clinical follow-up (FU) was at 10.3 years (range 1.5-15.6) for the SC and 12 years (range 0.2-16.2) for the FC group. Survivorship at 10 years was 100 % for the surface cemented trays and 93.3 % (95 % CI 80.5-100) for the fully cemented implants considering aseptic loosening as endpoint (p = 0.3918). Improvement of the AKS Score was greater in the SC group (p = 0.044) and patients in this group were more satisfied (p = 0.013). For any other clinical parameter, no difference could be observed (p > 0.05). CONCLUSION: Results of this study showed no statistically significant difference regarding long-term survivorship for the two cementing techniques. This finding questions the claimed advantage of full cementation for tibial components. The presented data do not support the concern that surface cementation results in insufficient fixation in patients with rheumatoid arthritis.
25711874 A maximum difference scaling survey of barriers to intensive combination treatment strateg 2015 May The objectives of the study were to determine the relative importance of barriers related to the provision of intensive combination treatment strategies with glucocorticoids (ICTS-GCs) in early rheumatoid arthritis (ERA) from the rheumatologists' perspective and to explore the relation between rheumatologists' characteristics and importance scores. A maximum difference scaling (MDS) survey was administered to 66 rheumatologists in Flanders and the Brussels-Capital Region. The survey included 25 barriers, previously being discovered in a qualitative study. The survey included 25 choice sets, each of which contained a different set of four barriers. In each choice situation, respondents were asked to choose the most important barrier. The mean relative importance score (RIS) for each barrier was calculated using hierarchical Bayes modeling. The potential relation between rheumatologists' characteristics and the RIS was examined using Spearman's correlation coefficient, Mann-Whitney U test, and Kruskal-Wallis H test. The three highest ranked barriers included "contraindicated for some patients (e.g., patients with comorbidities, older patients)," "an increased risk of side effects and related complications," and "patients' resistance" with a mean ± SD RIS of 9.76 ± 0.82, 8.50 ± 1.17, and 7.45 ± 1.22, respectively. Comparing the RISs based on rheumatologists' characteristics, a different ranking was found for three barriers depending on the age, university location, and/or frequency of prescribing ICTS-GCs. The dominant barriers hindering ICTS-GCs prescription from a rheumatologists' perspective are patient-related barriers and barriers related to the complexity of prescribing a combination therapy including GCs. A tailored improvement intervention is needed to overcome these barriers and should focus on the familiarity of rheumatologists with ICTS-GC and patient education.
25801883 From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the tre 2015 Apr Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the 'active ingredients'. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and γδT cell-dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action.
26991245 Effect of Drug Therapy on Net Cholesterol Efflux Capacity of High-Density Lipoprotein-Enri 2016 Sep OBJECTIVE: Patients with rheumatoid arthritis (RA) have an increased risk of coronary heart disease (CHD). Some RA therapies may modify this risk, but the underlying mechanisms are unclear. The cholesterol efflux capacity of high-density lipoprotein (HDL) is associated with a reduced CHD risk in non-RA populations; however, inflammation may impair the function of HDL. The aim of this study was to evaluate whether reduced inflammation resulting from treatment with methotrexate (MTX), adalimumab (ADA), or tocilizumab (TCZ) would increase the net cholesterol efflux capacity of HDL in patients with RA. METHODS: A longitudinal multicenter study repository (Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository) provided clinical information for and serum samples from 70 patients with RA before and 6 months after starting treatment with a new drug (MTX [n = 23], ADA [n = 22], or TCZ [n = 25]). Disease activity was measured using the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). The net cholesterol efflux capacity was measured in paired serum samples using THP-1 macrophages, and total cellular cholesterol was measured by fluorometric assay. RESULTS: The DAS28-ESR decreased with all treatments (P < 0.001). Net cholesterol efflux capacity was not significantly changed after 6 months of new RA therapy (mean ± SD 36.9 ± 17.3% units at baseline versus 38.0% ± 16.9% units at 6 months [P = 0.58]). However, change in net cholesterol efflux capacity was associated with change in the DAS28-ESR (ρ = -0.25, P = 0.04). In a post hoc analysis of patients with impaired net cholesterol efflux capacity at baseline, treatment with TCZ resulted in significant improvement in net cholesterol efflux capacity (21.9 ± 14.7% units at baseline versus 31.3% ± 12.8% units at 6 months [P < 0.02]), but this was not observed with MTX or ADA. CONCLUSION: Net cholesterol efflux capacity of HDL cholesterol did not change significantly after 6 months of new RA therapy, except in patients with impaired baseline cholesterol efflux capacity who were receiving TCZ. Change in disease activity was associated with change in the net cholesterol efflux capacity.
30641006 [Efficacy of Hebi Formula Combined Methotrexate on Early Rheumatoid Arthritis Patients wit 2016 Oct Objective To observe the efficacy of Hebi Formula (HF) combined Methotrexate (MTX) on early rheumatoid arthritis (RA) patients with disharmony of Gan and Pi syndrome (DGPS) and its effects on matrix metalloproteinase-3 (MMP-3) activator of nuclear factor-KB/receptor activator of nu- clear factor-KB/osteoprotegerin (RANK/RANKL/OPG). Methods Totally 72 early RA patients with DGPS were assigned to the treatment group and the control group according to random digit table, 36 in each group. Patients in the control group took MTX, while those in the treatment group additionally took HF. MTX dose was increased from 7. 5 mg to 12. 5 mg gradually, once per week, and the course of treatment was 24 weeks. Efficacy for Chinese medicine (CM) syndromes, ACR20 improvement rate, laboratory re- lated indices [ rheumatoid factor ( RF ) , erythrocyte sedimentation rate ( ESR ) , C-reactive protein (CRP) , anti-cyclic citrullinated peptide antibody (CCP)], serum levels of MMP-3, OPG, RANKL, and adverse reactions were observed. Results The standard arriving rate of ACR20 was 82. 86% (2935) in the treatment group, higher than that in the control group [51. 52% (173) ;P <0. 05). The effective rate of CM syndrome was 85. 7% (30f35) in the treatment group, higher than that in the control group [63. 6% (21/33) ;P <0. 05). Compared with before treatment in the same group, levels of RF,ESR,CRP,MMP-3, and RANKL decreased, the OPG level increased in the two groups after treatment (P <0. 05, P <0. 01). Compared with the control group, levels of RF, ESR, CRP, and RANKL all decreased with statistical difference (P <0. 01 , P <0. 05). Liver dysfunction occurred in 1 case of the treatment group. Leucopenia occurred in 1 case and liver dysfunction occurred in 2 cases of the control group. Conclusion HF com- bined MTX could improve symptoms of early RA patients with DGPS, and regulate bone destruction in- duced by RANK/RANKL/OPG systems.
26138292 Role of Bcl-3 in the development of follicular helper T cells and in the pathogenesis of r 2015 Oct OBJECTIVE: We have previously shown that expression of the Bcl-3 gene, a member of the IκB family, is down-regulated in CD4+ T cells from patients with rheumatoid arthritis (RA) following tocilizumab therapy. The objective of this study was to examine the role of Bcl-3 in the pathogenesis of RA. METHODS: DNA microarray analysis was used to compare the signal intensity of Bcl-3 in CD4+ T cells from untreated RA patients and healthy controls. We examined the roles of interleukin-6 (IL-6)/STAT-3 signaling in the induction of Bcl-3. In addition, we analyzed the gene expression profiles of Bcl-3-transduced CD4+ T cells by RNA sequencing. The effects of enforced expression as well as gene silencing of Bcl-3 on the development of follicular helper T (Tfh) cells were evaluated. Finally, we examined correlations between the signal intensities of Bcl-3 and Tfh cell-related genes in CD4+ T cells from untreated RA patients. RESULTS: Bcl-3 levels were significantly higher in RA patients than in healthy controls. IL-6 induced Bcl-3 expression in CD4+ T cells in a STAT-3-dependent manner. Transcriptome analysis revealed that the expression of Bcl-6, a master regulator of Tfh cell differentiation, was significantly up-regulated by the enforced Bcl-3 expression. The enforced Bcl-3 expression increased, but Bcl-3 silencing decreased, the numbers of IL-21-producing Tfh-like cells. Bcl-3 levels in CD4+ T cells from RA patients correlated positively with the levels of Tfh cell-related genes CXCR5, inducible costimulator, and achaete-scute homolog 2. CONCLUSION: Bcl-3 is involved in the development of Tfh cells and the pathogenesis of RA, presumably by inducing IL-21 production.
26238767 Decoy receptor 3 regulates the expression of tryptophan hydroxylase 1 in rheumatoid synovi 2015 Oct Decoy receptor 3 (DcR3) is expressed in rheumatoid arthritis fibroblast‑like synoviocytes (RA‑FLS) and downregulates the expression of tryptophan hydroxylase 1 (TPH1), which is the rate‑limiting enzyme in serotonin synthesis. The aim of the present study was to determine the specificity of the effects of DcR3 on TPH1 in RA‑FLS, and therefore determine whether DcR3 had the potential to modulate the pathogenesis of RA. The present study also aimed to compare the effects of DcR3 and inflammatory cytokines on the expression of TPH1 in RA‑FLS and osteoarthritis (OA)‑FLS. Primary cultured RA‑ or OA‑FLS were incubated with 1.0 µg/ml DcR3‑Fc protein or 1.0 µg/ml control immunoglobulin G (IgG)1 for 12 h, or with 1.0 ng/ml tumor necrosis factor (TNF)α, 1.0 ng/ml interleukin (IL)‑1β or serum‑free Opti‑MEM only, for 24 h. The relative mRNA expression levels of TPH1 were subsequently quantified using reverse transcription‑polymerase chain reaction. The expression of serotonin in RA or OA synovial tissue was detected using immunohistochemistry. The mRNA expression of TPH1 was observed in both RA‑ and OA‑FLS and was significantly decreased following treatment with DcR3 in the RA‑FLS, however, not in the OA‑FLS. The mRNA expression of TPH1 was significantly decreased following treatment with TNFα or IL‑1β in both the RA‑ and OA‑FLS. The expression of serotonin in the multi‑layered lining synovial cells of RA and the outer layer lining synovial cells of OA was detected using immunohistochemistry. The present study is the first, to the best of our knowledge, to demonstrate that the expression of TPH1 in FLS is downregulated by inflammatory cytokines, and that DcR3 suppressed the expression of TPH1 in RA‑FLS in a disease‑specific manner. These results suggested that synovial serotonin may be involved in the pathogenesis of RA, and that TPH1 and DcR3 may be potential therapeutic targets for the treatment of RA.