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ID PMID Title PublicationDate abstract
28681371 Breast Cancer in Patients of Rheumatoid Arthritis with Methotrexate Therapy Mimicking Hist 2017 Jul 20 Two breast cancer patients with a history of treatment for long-term rheumatoid arthritis (RA) had histological findings similar to histological changes seen in resected mammary gland specimens following neoadjuvant chemotherapy (NAC). The first patient was a 64-year-old woman who visited our hospital after feeling a lump in her left breast. The second patient was a 68-year-old woman who visited our hospital for an indentation in her left nipple. They were diagnosed with breast cancer following detailed examinations and underwent mastectomy. Both patients had a history of RA and were being treated with Methotrexate. The histological diagnoses of these patients were invasive ductal carcinoma, but frequent dispersal of cancer cell nests, stromal fibrosis, elastosis, edema and inflammatory cell infiltration were seen. Fibrosis was also found in the dissected lymph node. These histological findings were extremely similar to changes that occur in the mammary gland tissue after NAC; however, these patients had not undergone NAC. Methotrexate, which was being administered as an anti-rheumatic drug to the two patients, might have played a role similar to that of metronomic chemotherapy, which involves the continuous use of low-dose anti-cancer drugs, resulting in histological changes similar to those seen after NAC.
28718078 Relationship between daily pain and affect in women with rheumatoid arthritis: lower optim 2018 Feb The aim of the study was to examine the moderating effect of optimism on the relationship between daily pain-daily affect. Fifty-four female patients with rheumatoid arthritis completed self-report measures of optimism (once), daily pain and daily positive and negative affect for 7 consecutive days during hospitalization. Results of multilevel random coefficients modeling demonstrated a significant cross-level interaction for daily negative affect only. Simple slopes analysis revealed that low optimism was related to a stronger positive relationship between daily pain and daily negative affect, whereas this effect was insignificant for higher optimism. High optimism was also related to higher daily positive affect, regardless of pain level. These findings suggest that low optimism may be a vulnerability factor in the daily pain-daily affect relationship rather than high optimism acting as a protective factor.
27830964 Fcγ receptor 3B polymorphism is associated with hypersensitivity reactions to adalimumab 2017 Sep OBJECTIVES: To examine the association between Fcγ receptor (FcγR) polymorphisms and the development of hypersensitivity reactions to adalimumab in patients with rheumatoid arthritis. METHODS: Sixty-five patients receiving adalimumab were enrolled in the study. Genetic polymorphisms for FcγR3B were genotyped in FCGR3B NA1/2 alleles by real allelic discrimination assay. Clinical information and the occurrence of a hypersensitivity reaction to adalimumab were collected from the patients' charts. RESULTS: A hypersensitivity reaction was observed in 12% of the patients. Clinical information obtained from patients with a reaction and those without were the same. The FCGR3B NA1/NA1, NA1/NA2, and NA2/NA2 alleles were found in 75%, 13%, and 13% of the patients with hypersensitivity reaction, respectively, and in 28%, 42%, and 30% of those without a hypersensitivity reaction, respectively (p = 0.04). Multivariate logistic regression analysis identified only the NA1/NA1 as an independent relevant factor for a hypersensitivity reaction to adalimumab (OR 7.7, p = 0.01). CONCLUSIONS: The FCGR3B NA1/NA1 genotype is associated with hypersensitivity reactions to adalimumab.
28645978 Model-based methods for case definitions from administrative health data: application to r 2017 Jun 23 OBJECTIVE: This research proposes a model-based method to facilitate the selection of disease case definitions from validation studies for administrative health data. The method is demonstrated for a rheumatoid arthritis (RA) validation study. STUDY DESIGN AND SETTING: Data were from 148 definitions to ascertain cases of RA in hospital, physician and prescription medication administrative data. We considered: (A) separate univariate models for sensitivity and specificity, (B) univariate model for Youden's summary index and (C) bivariate (ie, joint) mixed-effects model for sensitivity and specificity. Model covariates included the number of diagnoses in physician, hospital and emergency department records, physician diagnosis observation time, duration of time between physician diagnoses and number of RA-related prescription medication records. RESULTS: The most common case definition attributes were: 1+ hospital diagnosis (65%), 2+ physician diagnoses (43%), 1+ specialist physician diagnosis (51%) and 2+ years of physician diagnosis observation time (27%). Statistically significant improvements in sensitivity and/or specificity for separate univariate models were associated with (all p values <0.01): 2+ and 3+ physician diagnoses, unlimited physician diagnosis observation time, 1+ specialist physician diagnosis and 1+ RA-related prescription medication records (65+ years only). The bivariate model produced similar results. Youden's index was associated with these same case definition criteria, except for the length of the physician diagnosis observation time. CONCLUSION: A model-based method provides valuable empirical evidence to aid in selecting a definition(s) for ascertaining diagnosed disease cases from administrative health data. The choice between univariate and bivariate models depends on the goals of the validation study and number of case definitions.
27539651 Musculoskeletal ultrasonography delineates ankle symptoms in rheumatoid arthritis. 2017 May OBJECTIVES: To clarify the use of musculoskeletal ultrasonography (US) of ankle joints in rheumatoid arthritis (RA). METHODS: Consecutive RA patients with or without ankle symptoms participated in the study. The US, clinical examination (CE), and patients' visual analog scale for pain (pVAS) for ankles were assessed. Prevalence of tibiotalar joint synovitis and tenosynovitis were assessed by grayscale (GS) and power Doppler (PD) US using a semi-quantitative grading (0-3). The positive US and CE findings were defined as GS score ≥2 and/or PD score ≥1, and joint swelling and/or tenderness, respectively. Multivariate analysis with the generalized linear mixed model was performed by assigning ankle pVAS as a dependent variable. RESULTS: Among a total of 120 ankles from 60 RA patients, positive ankle US findings were found in 21 (35.0%) patients. The concordance rate of CE and US was moderate (kappa 0.57). Of the 88 CE negative ankles, US detected positive findings in 9 (10.2%) joints. Multivariate analysis revealed that ankle US, clinical disease activity index, and foot Health Assessment Questionnaire, but not CE, was independently associated with ankle pVAS. CONCLUSION: US examination is useful to illustrate RA ankle involvement, especially for patients who complain ankle pain but lack CE findings.
28463029 High rate of improvement in serum matrix metalloproteinase-3 levels at 4 weeks predicts re 2018 Jan OBJECTIVE: This study aimed to determine whether serum matrix metalloproteinase-3 (MMP-3) levels can predict remission in rheumatoid arthritis (RA) patients treated with adalimumab (ADA). METHODS: Subjects were 114 RA patients continuously treated with ADA for 52 weeks. Predictive factors at baseline and 4 weeks after initiation of ADA therapy for the achievement of remission (28-point count Disease Activity Score-CRP (DAS28-CRP) < 2.3) at 52 weeks were evaluated by multivariate logistic regression analysis. RESULTS: DAS28-CRP at 4 weeks (odds ratio (OR) 0.614, 95% confidence interval (CI) 0.382-0.988) and improvement in serum MMP-3 levels at 4 weeks (OR 1.057, 95% CI 1.002-1.032) were independent predictors of remission at 52 weeks. The best cut-off level of DAS28-CRP and improvement in serum MMP-3 levels at 4 weeks for predicting remission at 52 weeks was 3.73 (sensitivity: 90%, specificity: 50%, area under the receiver operating characteristic curve (AUC): 62%) and 39.93% (sensitivity: 47%, specificity: 83%, AUC: 64%), respectively. CONCLUSION: Our findings suggest that a high rate of improvement in serum MMP-3 levels at 4 weeks after initiation of ADA therapy can predict remission at 52 weeks in RA patients.
28765254 Risk of Obstructive Sleep Apnea and Its Association with Cardiovascular and Noncardiac Vas 2018 Jan OBJECTIVE: To define the incidence of obstructive sleep apnea (OSA) in patients with rheumatoid arthritis (RA) and determine whether OSA diagnosis predicts future cardiovascular disease (CVD) and noncardiac vascular events. METHODS: Medical information pertaining to RA, OSA, CVD, and vascular diagnoses was extracted from a comprehensive medical record system for a geographically defined population of 813 patients previously diagnosed with RA and 813 age- and sex-matched comparator subjects. RESULTS: The risk for OSA in persons with RA versus comparators was elevated, although not reaching statistical significance (HR 1.32, 95% CI 0.98-1.77; p = 0.07). Patients with RA were more likely to be diagnosed with OSA if they had traditional risk factors for OSA, including male sex, current smoking status, hypertension, diabetes, dyslipidemia, and increased body mass index. Features of RA disease associated with OSA included large joint swelling and joint surgery. Patients with RA with decreased renal function were also at higher risk of OSA. The increased risk of overall CVD among patients with RA who have OSA was similar to the increased CVD risk associated with OSA in the comparator cohort (interaction p = 0.86). OSA diagnosis was associated with an increased risk of both CVD (HR 1.9, 95% CI 1.08-3.27), and cerebrovascular disease (HR 2.4, 95% CI 1.14-5.26) in patients with RA. CONCLUSION: Patients with RA may be at increased risk of OSA secondary to both traditional and RA-related risk factors. Diagnosis with OSA predicts future CVD in RA and may provide an opportunity for CVD intervention.
28889208 Detection of human antibodies binding with smooth and rough LPSs from Proteus mirabilis O3 2017 Nov Bacteria of the genus Proteus of the family Enterobacteriaceae are facultative human pathogens responsible mainly for urinary tract and wound infections, bacteremia and the development of rheumatoid arthritis (RA). We have analyzed and compared by ELISA the titer of antibodies in plasmas of healthy individuals and in sera of rheumatoid arthritis patients recognizing a potential host cross-reactive epitope (lysine-galacturonic acid epitopes) present in Proteus lipopolysaccharide (LPS). In our experiments LPSs isolated from two mutants of smooth Proteus mirabilis 1959 (O3), i.e. strains R110 and R45, were used. R110 (Ra type mutant) is lacking the O-specific polysaccharide, but possesses a complete core oligosaccharide, while R45 (Re type) has a reduced core oligosaccharide and contains two 3-deoxy-D-manno-oct-2-ulosonic acid residues and one of 4-amino-4-deoxy-L-arabinopyranose residues. Titer of P. mirabilis S1959 LPS-specific-antibodies increased with the age of blood donors. RA and blood donors' sera contained antibodies against S and Ra and Re type of P. mirabilis O3 LPSs. Antibodies recognizing lysine-galacturonic acid epitopes of O3 LPS were detected by ELISA in some plasmas of healthy individuals and sera of rheumatoid arthritis patients. RA patients antibodies reacting with P. mirabilis S1959 S and R LPSs may indicate a potential role of anti-LPS antibodies in molecular mimicry in RA diseases.
29155458 Localization of surfactant protein-D in the rheumatoid synovial membrane. 2018 Jan Surfactant protein-D (SP-D) is a collectin, which plays an important role in airway protection and inflammation. The molecule has both pro- and anti-inflammatory capacities depending on its molecular size. Its involvement in joint diseases is largely unknown and the aim of this investigation was to study SP-D occurrence and distribution in the synovial membrane of patients with long-standing rheumatoid arthritis (RA) and osteoarthritis (OA). Six RA patients and six OA patients, who underwent total hip arthroplasty, were included in the study. Synovial tissue biopsies were obtained during surgery and subsequently prepared for immunohistochemistry. In this first, small-scale comparative study on the occurrence of SP-D in the synovial membrane of RA and OA, we report that SP-D was only present in the microvascular endothelium in subsynovial and pannus tissue and that the immunostaining was much stronger than in OA. This distribution pattern suggests that SP-D modulates RA inflammatory activities.
28611080 Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-r 2017 Oct OBJECTIVES: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs). METHODS: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests. RESULTS: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs. CONCLUSIONS: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand. TRIAL REGISTRATION NUMBER: NCT00660647.
28222785 TCD4(pos) lymphocytosis in rheumatoid and psoriatic arthritis patients following TNFα blo 2017 Feb 21 BACKGROUND: Lymphocyte expansion and true lymphocytosis are commonly observed in the everyday clinical practice. The meaning of such phenomenon is often poorly understood so that discrimination between benign and malignant lymphocytosis remains difficult to establish. This is mainly true when lymphocytosis rises in patients affected by immune-mediated chronic inflammatory diseases under immunosuppressive treatment, conditions potentially associated with lymphomagenesis. In this brief report the development of mild T CD4(pos) lymphocytosis in a group of patients with chronic arthritis under anti-TNF-α treatment is described. METHODS: Two hundred eight rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients have been evaluated longitudinally for at least 1-year before and 2-years after anti-TNF-α therapy introduction for the possible appearance of a lymphocyte expansion. In patients who developed lymphocyte expansion, T, B and NK cells were analysed. RESULTS: Twenty-five out of 208 (12%) subjects developed a mild T CD4(pos) lymphocytosis, during anti-TNF-α therapy, which reverted after its interruption. Higher lymphocyte count, more frequent use of steroids and shorter disease duration, before biological therapy start, have emerged as risk factors for lymphocytosis development. CONCLUSIONS: This is the first longitudinal cohort study evaluating the onset of lymphocytosis in RA and PsA patients under anti-TNF-α treatment and its possible clinical relevance. A mild T CD4(pos) lymphocytosis has been observed in 12% of RA and PsA patients probably related to anti-TNF-α treatment as previously reported by anecdotal cases. Patients with higher baseline lymphocyte count, use of steroids and shorter disease duration before the introduction of biologic therapy, seem to be prone to develop this laboratory reversible abnormality.
28914370 Thioredoxin 1 is associated with the proliferation and apoptosis of rheumatoid arthritis f 2018 Jan We aimed to investigate the possible effects of thioredoxin 1 (Trx1) on the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and elucidate the possible mechanisms involved. We investigated the distribution and expression of Trx1 in synovial tissues from RA and osteoarthritis (OA) patients by immunohistochemistry and real-time polymerase chain reaction (RT-PCR) analyses. RA-FLSs were isolated and cultured under normoxic (21% oxygen) or hypoxic (3% oxygen) concentrations. Transfection of Trx1-siRNAs and a Trx1 overexpression construct was conducted to manipulate the expression of Trx1. Protein expression was detected by Western blot. Doxorubicin (Adriamycin, ADR) was used to induce apoptosis. LY-294002 was used for the inhibition of PI3K-Akt. Cell proliferation and apoptosis were determined by MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt) assay and flow cytometry, respectively. The mRNA and protein expression of Trx1 in RA tissues was higher than that in OA tissues. The expression levels of Trx1 and cell proliferation in RA-FLSs were increased under hypoxia in comparison to those under normoxia. In hypoxia, downregulation of Trx1 significantly suppressed FLS proliferation, and the expression of PI3Kp85, phospho-Akt, and Bcl-2, while notably increased FLS apoptosis and the expression of active Caspase3 and Bax. In normoxia, Trx1 overexpression promoted the FLS proliferation and the expression of PI3Kp85, phospho-Akt, and Bcl-2, but inhibited FLS apoptosis and the expression of active Caspase3 and Bax in FLSs. Such effects were partially repressed by LY-294002 treatment. Trx1 may play an important role in regulating the proliferation and apoptosis of RA-FLSs by modulating PI3K-Akt activation.
28371624 Dextran sulfate nanoparticles as a theranostic nanomedicine for rheumatoid arthritis. 2017 Jul With the aim of developing nanoparticles for targeted delivery of methotrexate (MTX) to inflamed joints in rheumatoid arthritis (RA), an amphiphilic polysaccharide was synthesized by conjugating 5β-cholanic acid to a dextran sulfate (DS) backbone. Due to its amphiphilic nature, the DS derivative self-assembled into spherical nanoparticles (220 nm in diameter) in aqueous conditions. The MTX was effectively loaded into the DS nanoparticles (loading efficiency: 73.0%) by a simple dialysis method. Interestingly, the DS nanoparticles were selectively taken up by activated macrophages, which are responsible for inflammation and joint destruction, via scavenger receptor class A-mediated endocytosis. When systemically administrated into mice with experimental collagen-induced arthritis (CIA), the DS nanoparticles effectively accumulated in inflamed joints (12-fold more than wild type mice (WT)), implying their high targetability to RA tissues. Moreover, the MTX-loaded DS nanoparticles exhibited significantly improved therapeutic efficacy against CIA in mice compared to free MTX alone. Overall, the data presented here indicate that DS nanoparticles are potentially useful nanomedicines for RA imaging and therapy.
28328159 Improved disease activity with fosdagrocorat (PF-04171327), a partial agonist of the gluco 2017 Aug AIM: To assess efficacy and safety of fosdagrocorat (PF-04171327), a potential dissociated agonist of the glucocorticoid receptor, in rheumatoid arthritis (RA) patients. METHODS: This multicenter, double-blind, parallel-group, active- and placebo-controlled Phase 2 study (NCT00938587) randomized 86 patients (1 : 1 : 1 : 1) to receive fosdagrocorat 10 mg, fosdagrocorat 25 mg, prednisone 5 mg or placebo, all with stable background methotrexate therapy. The primary outcome was change from baseline in Disease Activity Score of 28 joints (DAS28-4[C-reactive protein (CRP)]) after 2 weeks of treatment. Secondary outcomes included American College of Rheumatology (ACR) response rates, change from baseline in ACR core components and Health Assessment Questionnaire Disability Index. RESULTS: At week 2, improvements from baseline in DAS28-4(CRP) with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo were -1.69, -2.22, -1.17 and -0.96, respectively, and were statistically significantly greater for both fosdagrocorat doses versus placebo (P < 0.05) and for fosdagrocorat 25 mg versus prednisone 5 mg (P < 0.001). The effects of fosdagrocorat on secondary outcomes were generally consistent with those observed for the primary outcome. Adverse events (AEs) were reported for eight (38%), three (14%), four (19%) and 12 (55%) patients treated with fosdagrocorat 10 and 25 mg, prednisone 5 mg and placebo, respectively. Most AEs were mild in severity. Four patients discontinued treatment due to AEs (fosdagrocorat 10 mg, n = 2; placebo, n = 2). There were no serious AEs. CONCLUSION: Fosdagrocorat 10 and 25 mg demonstrated efficacy in improving signs and symptoms in RA patients, with manageable AEs. Additional studies are needed to assess the longer-term safety and efficacy of fosdagrocorat.
28096457 The predictive value of serum S100A9 and response to etanercept is not confirmed in a larg 2017 Jun 1 OBJECTIVE: The aim was to correlate protein concentrations of S100A9 in pretreatment serum samples with response to the tumour-necrosis factor (TNF) inhibitor drugs etanercept in a large UK replication cohort. METHODS: Pretreatment serum samples from patients with RA (n = 236) about to commence treatment with etanercept had S100A9 serum concentration measured using an ELISA. Following the experimental procedure, S100A9 concentrations were analysed with respect to EULAR response. RESULTS: No evidence of association between S100A9 concentration and EULAR response to the TNF-inhibitor biologic drug etanercept was observed following multinomial logistic regression analysis (non-responder vs moderate responder, P = 0.957; and non-responder vs good responder, P = 0.316). Furthermore, no significant associations were observed when correlating pretreatment S100A9 concentrations with clinical parameters of disease activity (P > 0.05). CONCLUSION: In the largest replication cohort conducted to date, no evidence for association was observed to support the use of S100A9 as a clinical biomarker predictive of response to the TNF-inhibitor biologic drug etanercept.
28841649 Glycoprotein YKL-40: A potential biomarker of disease activity in rheumatoid arthritis dur 2017 OBJECTIVE: YKL-40, a chitinase-like glycoprotein associated with inflammation and tissue remodeling, is produced by joint tissues and recognized as a candidate auto-antigen in rheumatoid arthritis (RA). In the present study, we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aiming for early remission. METHODS: Ninety-nine patients with early DMARD-naïve RA participated in the NEO-RACo study. For the first four weeks, the patients were treated with the combination of sulphasalazine, methotrexate, hydroxychloroquine and low dose prednisolone (FIN-RACo DMARD combination), and subsequently randomized to receive placebo or infliximab added on the treatment for further 22 weeks. Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay. RESULTS: At the baseline, plasma YKL-40 concentration was 57 ± 37 (mean ± SD) ng/ml. YKL-40 was significantly associated with the disease activity score, interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks' treatment. The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment, and there was no further reduction when the tumour necrosis factor-α antagonist infliximab was added on the combination treatment. CONCLUSIONS: High YKL-40 levels were found to be associated with disease activity in early DMARD-naïve RA and during intensive treat-to-target therapy. The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission.
28549945 Validity of the rheumatoid arthritis impact of disease (RAID) score and definition of cut- 2018 May OBJECTIVES: To assess the validity of the rheumatoid arthritis impact of disease (RAID) for measuring disease activity of rheumatoid arthritis (RA) and to determine cut-off values for defining the disease activity states. METHODS: A total of 622 RA patients from an European database have been included. Cross-validation was based on assessment of convergent and discriminant validity. Optimal cut-offs were determined against external criteria by calculating the respective 25th and 75th percentiles mean values of RAID. External criteria included definitions for remission (REM), low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA), cut-offs of the 28-joint disease activity score-C-reactive protein (DAS28-CRP) score. RESULTS: The RAID showed a moderate degree of correlation with respect to DAS28-CRP (rho=0.417; P<0.0001). The receiver operating characteristic (ROC) curves to discriminate the ability of RAID to distinguish patients with active and non-active disease was very good with an area under the curve (AUC) of 0.847 (95% confidence interval [CI]: 0.816 to 0.878; P<0.0001). Based on the distributions of RAID in the different disease activity groups, we propose the following cut-off values for REM: RAID ≤3; for LDA: RAID >3 and ≤4; for MDA: RAID >4 and ≤6; for HDA: RAID >6. Mean RAID differed significantly between patients classified as REM, LDA, MDA or HDA (P=0.001). CONCLUSIONS: The cut-offs revealed good measurement characteristics in cross-validation analysis, had great discriminatory performance in distinguishing patients with different levels of disease activity and are suited for widespread use in everyday practice application and research.
28511719 Interleukin-10-producing LAG3(+) regulatory T cells are associated with disease activity a 2017 May 16 BACKGROUND: Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4(+)CD25(-)LAG3(+) T cells (LAG3(+) Tregs) and their association with rheumatoid arthritis (RA). METHODS: LAG3(+) Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3(+) Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4(+) T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays. RESULTS: LAG3(+) Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25(+) Tregs. Cell-to-cell contact was required for the suppressive function of LAG3(+) Tregs. The frequency of LAG3(+) Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3(+) Tregs significantly increased after 6 months of abatacept treatment, whereas CD25(+) Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4(+) T cells, and abatacept-treated CD4(+) T cells exhibited suppressive activity. CONCLUSIONS: IL-10-producing LAG3(+) Tregs are associated with the immunopathology and therapeutic response in RA. LAG3(+) Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.
28978936 Functional role of PPAR-γ on the proliferation and migration of fibroblast-like synoviocy 2017 Oct 4 Peroxisome proliferator-activated receptor (PPAR)-γ is involved in both normal physiological processes and pathology of various diseases. The purpose of this study was to explore the function and underlying mechanisms of PPAR-γ in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) proliferation and migration. In the present study, we found PPAR-γ expression was remarkably reduced in RA synovium patient compare with OA and normal, as well as it was low-expression in Adjuvant-induced arthritis (AA). Moreover, inhibition PPAR-γ expression by T0070907 (12.5 μM) or PPAR-γ siRNA could promote FLSs proliferation and expressions of c-Myc, Cyclin D1, MMP-1, and MMP-9 in AA FLSs, except for TIPM-1. These date indicate that up-regulation of PPAR-γ may play a critical role in RA FLSs. Interestingly, co-incubation FLSs with Pioditazone (25 μM) and over expression vector with pEGFP-N1-PPAR-γ reduced proliferation and expressions of c-Myc, Cyclin D1, MMP-1, and MMP-9 in AA FLSs, besides TIMP-1. Further study indicates that PPAR-γ may induce activation Wnt/β-catenin signaling. In short, these results indicate that PPAR-γ may play a pivotal role during FLSs activation and activation of Wnt/β-catenin signaling pathway.
28681901 Dense Genotyping of Immune-Related Regions Identifies Loci for Rheumatoid Arthritis Risk a 2017 Sep Over 100 risk loci for rheumatoid arthritis (RA) have been identified in individuals of European and Asian descent, but the genetic basis for RA in African Americans is less well understood. We genotyped 610 African Americans with autoantibody positive RA and 933 African American controls on the ImmunoChip (iChip) array. Using multivariable regression we evaluated the association between iChip markers and the risk of RA and radiographic severity. The single nucleotide polymorphism (SNP) rs1964995 (OR = 1.97, p = 1.28 × 10(-15)) near HLA-DRB1 was the most strongly associated risk SNP for RA susceptibility; SNPs in AFF3, TNFSF11, and TNFSF18 loci were suggestively associated (10(-4) < p < 3.1 × 10(-6)). Trans-ethnic fine mapping of AFF3 identified a 90% credible set containing previously studied variants including rs9653442, rs7608424, and rs6712515 as well as the novel candidate variant rs11681966; several of these likely influence AFF3 gene expression level. Variants in TNFRSF9, CTLA4, IL2RA, C5/TRAF1, and ETS1 - but no variants within the major histocompatibility complex - were associated with RA radiographic severity. Conditional regression and pairwise linkage disequilibrium (LD) analyses suggest that additional pathogenic variants may be found in ETS1 and IL2RA beyond those found in other ethnicities. In summary, we use the dense genotyping of the iChip array and unique LD structure of African Americans to validate known risk loci for RA susceptibility and radiographic severity, and to better characterize the associations of AFF3, ETS1, and IL2RA.