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ID PMID Title PublicationDate abstract
27079198 Expression of miR-146a, miR-155, and miR-223 in formalin-fixed paraffin-embedded synovial 2016 Jul Rheumatoid arthritis (RA) is a chronic autoimmune disease with a heterogeneous clinical presentation affecting about 1 % of adults in developed countries. Currently, the diagnosis is based on the revised criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) from 2010. These criteria include clinical and laboratory parameters. Because of the variability of the clinical picture, delayed diagnosis of RA occurs in a significant subset of patients. Therefore, the discovery of novel biomarkers that improve the diagnosis of RA is of particular interest. Recently, it became evident that miRNAs have regulatory activities in physiologic processes and human diseases. Upregulation of miR-146a, miR-155, and miR-223 has been shown in various compartments such as serum, blood, synovial fluid, and tissues in patients with RA. A total of 87 samples were analyzed (RA 50, osteoarthritis (OA) 37). RNA was isolated from formalin-fixed paraffin-embedded synovial tissue (FFPE). The relative expression of miR-146a, miR-155, and miR-223 was determined by comparison to a housekeeping RNA molecule (snRNA U6) and an RNA pool from histologically and clinically verified OA samples. miR-146a, miR-155, and miR-223 were significantly elevated in RA compared to OA synovial tissues (p < 0.001). A strong correlation between the miRNAs could be observed. The sensitivity and specificity for the detection of RA were 0.76/0.80 (miR-146a), 0.80/0.95 (miR-155), and 0.86/0.81 (miR-223). The combination of miR-155 and miR-223 resulted in the highest area under the curve (AUC 0.92) with a sensitivity and specificity of 0.84/0.91, respectively. Significantly higher expression levels of miR-146a, miR-155, and miR-223 in FFPE synovial tissue samples of patients with established RA compared to patients with OA were shown. The usefulness of these miRs for the differential diagnosis of early phases of RA against OA remains to be investigated.
27009827 The influence of patient perceptions of disease on medication intensification in daily pra 2016 Nov OBJECTIVE: The objectives of this study were twofold: to assess if there are independent effects of variables representing patients' perceptions of disease on intensification of drug therapy in patients with RA seen in daily practice; and to test the hypothesis that effects of patients' perceptions of disease are mediated through patient self-reported willingness to alter therapy. METHODS: Before being seen by a physician, consecutive patients with RA, attending the Radboudumc outpatient rheumatology clinic, were asked to fill out a short questionnaire regarding the following four items: perceived health change, satisfaction with current health, willingness to change therapy and expected health change until the next visit. Independent associations between these measures, registered clinical measures and synthetic DMARD/biologic DMARD (including CSs) intensification were studied with logistic regression. Mediation analysis was performed focusing on the strongest predictor and self-reported willingness as a mediator. RESULTS: Out of 453 patients with RA, 65% female, 67% RF positive, medication was intensified for 82 patients (18%). All patient perception measures exhibited significant associations, independent of clinical measures, of which patient satisfaction with current health state was the strongest [odds ratio (OR) 0.21, 95% CI: 0.10, 0.44]. Significant mediation of the effect of patient satisfaction through willingness to alter therapy on actual registered medication intensification was found. CONCLUSION: Treat to Target interventions should address patients' perceptions of their disease, and the related health goals patients aim to achieve, in addition to the attained level of disease activity.
26982569 Smelling the Diagnosis: The Electronic Nose as Diagnostic Tool in Inflammatory Arthritis. 2016 OBJECTIVE: To investigate whether exhaled breath analysis using an electronic nose can identify differences between inflammatory joint diseases and healthy controls. METHODS: In a cross-sectional study, the exhaled breath of 21 rheumatoid arthritis (RA) and 18 psoriatic arthritis (PsA) patients with active disease was compared to 21 healthy controls using an electronic nose (Cyranose 320; Smiths Detection, Pasadena, CA, USA). Breathprints were analyzed with principal component analysis, discriminant analysis, and area under curve (AUC) of receiver operating characteristics (ROC) curves. Volatile organic compounds (VOCs) were identified by gas chromatography and mass spectrometry (GC-MS), and relationships between breathprints and markers of disease activity were explored. RESULTS: Breathprints of RA patients could be distinguished from controls with an accuracy of 71% (AUC 0.75, 95% CI 0.60-0.90, sensitivity 76%, specificity 67%). Breathprints from PsA patients were separated from controls with 69% accuracy (AUC 0.77, 95% CI 0.61-0.92, sensitivity 72%, specificity 71%). Distinction between exhaled breath of RA and PsA patients exhibited an accuracy of 69% (AUC 0.72, 95% CI 0.55-0.89, sensitivity 71%, specificity 72%). There was a positive correlation in RA patients of exhaled breathprints with disease activity score (DAS28) and number of painful joints. GC-MS identified seven key VOCs that significantly differed between the groups. CONCLUSIONS: Exhaled breath analysis by an electronic nose may play a role in differential diagnosis of inflammatory joint diseases. Data from this study warrant external validation.
26199061 Rituximab-induced serum sickness: A systematic review. 2015 Dec OBJECTIVES: To report a case of rituximab-induced serum sickness (RISS) and perform a systematic review and characterize RISS in autoimmune diseases and hematological malignancies. METHODS: A comprehensive search of MEDLINE, EMBASE, ACR, and EULAR databases was performed for relevant articles of patients with RISS from inception to September 2014. Statistical analysis of demographic and clinical features was performed using Microsoft EXCEL 2007 and SPSS version 20.0. RESULTS: In the 33 patients with RISS, the mean age of presentation was 39.1 ± 17.5yr with a female preponderance (n = 23, 76.67%). The majority of cases were associated with an underlying rheumatologic condition (n = 17, 51.5%), most commonly Sjögren's syndrome (n = 8, 44.4%). The classic triad of serum sickness (fever, rash, and arthralgia) was reported in 16 (48.5%) cases. Time from drug exposure to symptom onset was significantly greater with the first doses of rituximab compared to the second dose (mean time 10.00 vs. 4.05d, P = 0.002), and time to resolution was significantly greater for rheumatologic vs. hematological indications (mean time 2.50 vs. 1.00d, P = 0.035). Corticosteroids were the most commonly used treatment (n = 21), with all cases reporting a complete resolution of symptoms in 2.15 ± 1.34d. CONCLUSION: It is important to recognize RISS clinically, as it may mimic exacerbation of various rheumatologic conditions. Although RISS is typically self-limited, further infusions of rituximab should be avoided, as it may provoke more severe symptoms.
26172054 A Population-Based Study on the Association between Benign Prostatic Enlargement and Rheum 2015 Benign prostatic hyperplasia is one of the chronic inflammatory conditions in ageing male populations. Rheumatoid arthritis (RA) is a major autoimmune disease and is also regarded as a chronic inflammatory disorder. Although RA and benign prostatic enlargement (BPE) may share the same underlying etiologies, almost no study has ever attempted to explore the relationship between RA and BPE. The aim of this study was to explore the relationship between RA and BPE using a population-based dataset. This case-control study used data retrieved from the Taiwan Longitudinal Health Insurance Database 2005. This study comprised 18,716 patients with BPE and 18,716 age-matched patients without BPE. Conditional logistic regression analyses were performed to calculate the odds ratio (OR) for having been previously diagnosed with RA between patients with BPE and comparison patients. In total, 485 of the 37,432 sampled patients (1.3%) had received a prior RA diagnosis. There was a significant difference in the prevalence of prior RA between cases and controls (1.6% vs. 1.0%, p<0.001). After adjusting for patient's urbanization level, monthly income, geographic region, and obesity, the adjusted OR was 1.54 (95% CI = 1.28~1.85) for patients with BPE compared to comparison patients. In addition, the sensitivity analysis showed that BPE was consistently and significantly associated with a prior RA diagnosis even after excluding subjects diagnosed with RA within 1, 2, or 3 years prior to the index date (the adjusted ORs were 1.46, 1.50, and 1.42, respectively). We concluded that there was a significant association between prior RA and BPE. Further large-scale longitudinal studies are suggested to clarify the causal relationship between RA and BPE.
25490986 Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn? 2015 Feb There is increasing scientific interest in the field of vitamin D research, moving the focus beyond bone health to other disease processes. Low circulating vitamin D levels have been reported as a risk factor for several pathophysiologically divergent diseases, including cancers, diabetes, CVD, multiple sclerosis and inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD). But, therein, remains the challenge: can any single nutrient contribute to multiple complex disease mechanisms and, ultimately, have therapeutic potential? The aim of this review is to critically evaluate several strands of scientific evidence surrounding vitamin D and inflammation, primarily focusing on IBD. Epidemiological studies suggest an increased incidence of IBD and rheumatoid arthritis in countries of more northern latitudes, mirroring sunlight patterns. A considerable body of evidence supports the anti-inflammatory effects of vitamin D, at least in animal models of IBD. Although it is accepted that suboptimal vitamin D status is common in IBD, some studies suggest that this associates with more severe disease. With regard to treatment, the data are only beginning to emerge from randomised controlled trials to suggest that people with IBD may remain in remission longer when treated with oral vitamin D. In conclusion, several strands of evidence suggest that vitamin D may modify the immune response in IBD. There is a continued need for large well-designed clinical trials and mechanistic studies to determine if, and how, this emerging promise translates into tangible clinical benefits for people with chronic debilitating diseases such as IBD.
26314621 Latent Cytomegalovirus Infection in Rheumatoid Arthritis and Increased Frequencies of Cyto 2016 Feb OBJECTIVE: Leukocyte immunoglobulin-like receptor 1 (LIR-1) is up-regulated by cytomegalovirus (CMV), which in turn, has been associated with premature aging and more severe joint disease in patients with rheumatoid arthritis (RA). The aim of this study was to investigate the expression and functional significance of LIR-1 in CMV-positive RA patients. METHODS: We determined the phenotype, cytolytic potential, CMV-specific proliferation, and HLA-G-triggered, LIR-1-mediated inhibition of interferon-γ secretion of LIR-1+ T cells in RA patients and healthy controls. RESULTS: We found increased frequencies of CD8+ T cells with CMV pp65-specific T cell receptors in CMV-positive RA patients as compared to CMV-positive healthy controls. CMV-specific CD8+ T cells in these patients were preferentially LIR-1+ and exhibited a terminally differentiated polyfunctional phenotype. The numbers of LIR-1+CD8+ T cells increased with age and disease activity, and showed high levels of reactivity to CMV antigens. Ligation of LIR-1 with soluble HLA-G molecules in vitro confirmed an inhibitory role of the molecule when expressed on CD8+ T cells in RA patients. CONCLUSION: We propose that latent CMV infection in the context of a chronic autoimmune response induces the recently described "chronic infection phenotype" in CD8+ T cells, which retains anti-infectious effector features while exhibiting autoreactive cytolytic potential. This response is likely dampened by LIR-1 to avoid overwhelming immunopathologic changes in the setting of the autoimmune disease RA. The known deficiency of soluble HLA-G in RA and the observed association of LIR-1 expression with disease activity suggest, however, that LIR-1+ T cells are insufficiently controlled in RA and are still likely to be involved in the pathogenesis of the disease.
25565324 Anti-citrullinated peptide antibodies in Sudanese patients with Leishmania donovani infect 2015 Mar African patients with Leishmania donovani infections have signs of strong systemic inflammation and high levels of circulating immune complexes (IC) and rheumatoid factor (RF), all serologic markers of rheumatic disease. As inflammation in general is associated with citrullination, we sought to investigate ACPA responses in Sudanese Leishmania patients. Serum samples were collected from Sudanese patients with visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL) as well as from ACPA-positive Sudanese rheumatoid arthritis patients and compared to healthy Sudanese controls. Levels of circulating C1q-binding IC and anticyclic citrullinated peptide 2(CCP2) were investigated using ELISA, and RF was measured with nephelometry. C1q adsorption was carried out to investigate anti-CCP2 content in IC. Citrulline specificity was evaluated with control plates with cyclic arginine-containing control peptides. Leishmania-infected patients had elevated levels of RF and circulating IC but also a significant increase in anti-CCP2 (12%) as compared to healthy controls. Anti-CCP2-positive Leishmania patients displayed lower anti-CCP2 levels than Sudanese patients with rheumatoid arthritis (RA), and anti-CCP2 levels in Leishmania patients showed a continuum not resembling the dichotomous pattern seen in patients with RA. Whereas the anti-CCP reactivity of Sudanese RA sera was strictly citrulline dependent, anti-CCP2-positive Leishmania sera reacted equally well with ELISA plates containing arginine control peptides. There was a strong correlation between anti-CCP2 and circulating IC among the Leishmania patients, but IC depletion only marginally diminished anti-CCP2 levels. Our findings stress the importance to interpret a positive CCP test carefully when evaluated in non-rheumatic conditions associated with macrophage activation.
25817699 Positive association between serum thymic stromal lymphopoietin and anti-citrullinated pep 2015 Aug Thymic stromal lymphopoietin (TSLP) has been suggested recently to play an important role in the pathophysiology of rheumatoid arthritis (RA). However, there is little information on serum TSLP concentrations in RA and its clinical significance. The present study investigated whether serum TSLP concentrations were affected in patients with RA. Using an enzyme-linked immunosorbent assay (ELISA), we measured TSLP concentrations in the serum obtained from 100 patients with RA, 60 patients with osteoarthritis (OA) and 34 healthy volunteers. We also investigated the correlation between serum TSLP concentrations and clinical parameters of disease activity in RA [disease activity score using 28 joint counts (DAS28)-C-reactive protein (CRP), DAS28-erythrocyte sedimentation rate (ESR), Clinical Disease Activity Index (CDAI]), patient's/-physician's Visual Analogue Scale (VAS), swollen joints count, tender joints count, CRP, ESR and matrix metalloproteinase-3 (MMP-3) concentrations]. In addition, we investigated the correlation between serum TSLP concentrations and anti-citrullinated peptide antibody (ACPA) and serum tumour necrosis factor (TNF)-α. Serum TSLP levels in patients with RA were significantly higher than those in patients with OA and in healthy volunteers. Interestingly, serum TSLP concentrations were correlated significantly with ACPA titres, but not with other clinical parameters. There was a significant increase in serum TSLP concentrations in patients with RA, which was correlated positively with serum ACPA titres. These findings suggest that in patients with RA, TSLP may play a role in ACPA production by B cells.
26097194 Etanercept-Methotrexate Combination Therapy Initiators Have Greater Adherence and Persiste 2015 Dec OBJECTIVE: To estimate adherence and persistence with etanercept plus methotrexate (ETN-MTX) combination therapy and MTX, hydroxychloroquine, and sulfasalazine triple therapy at 1 year following treatment initiation in adults with rheumatoid arthritis (RA). METHODS: This retrospective analysis used data from the Truven Health MarketScan Commercial and Medicare Supplemental databases from January 2009 to July 2013. Adherence was defined as having percentage of days covered >80% for all drugs within each regimen. Persistence was defined as no treatment gap >45 days for any drug and no addition or switching to other disease-modifying antirheumatic drugs. Multiple logistic regression models were employed in the analyses to control for potential confounders. RESULTS: A total of 3,724 ETN-MTX patients and 818 triple therapy patients were eligible. At 1 year, 27.9% who were taking ETN-MTX and 18.2% using triple therapy were adherent to all agents in their regimen (P < 0.0001), and 29.4% who were taking ETN-MTX and 23.2% using triple therapy were persistent (P < 0.001). After adjusting for confounders, ETN-MTX patients had significantly greater odds of being adherent (odds ratio [OR] 1.79, 95% confidence interval [95% CI] 1.47-2.17) and persistent (OR 1.45, 95% CI 1.20-1.72) compared with patients using triple therapy. CONCLUSION: Patients with RA initiating treatment with ETN-MTX combination therapy demonstrated greater adherence and persistence at 1 year than patients initiating triple therapy.
27178986 Rheumatoid arthritis onset in postmenopausal women: Does the ACPA seropositive subset resu 2016 Aug 15 Rheumatoid arthritis (RA) incidence displays a differentiated age-dependent female-to-male ratio in which women outnumber men. Evidence that the peak incidence of RA in women coincides with menopause age, suggests a potential estrogenic role to disease etiology. Estrogens exert physiologically both stimulatory and inhibitory effects on the immune system. Epidemiologic and animal model studies with estrogen deprivation or supplementation suggested estrogens as to play, mainly, a protective role in RA immunopathology. In this review, we propose that some yet unidentified disturbances associated with estrogen circulating levels, differentiated by the menopausal status, play a major role in women's RA susceptibility. We focus on the interaction between estrogen deprivation and genetic risk alleles for anti-citrullinated protein antibodies (ACPA) seropositive RA, as a major driving force for increased immune reactivity and RA susceptibility, in postmenopausal women. This opens up new fields for research concerning the association among different irregular estrogenic conditions, the cytokine milieu, and age/menopausal status bias in RA.
27470609 Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control 2016 Nov INTRODUCTION: It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown. OBJECTIVE: To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. METHODS: We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. RESULTS: AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. CONCLUSION: There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.
25890584 Diffuse Myocardial Fibrosis and Inflammation in Rheumatoid Arthritis: Insights From CMR T1 2015 May OBJECTIVES: The goal of this study was to assess the diffuse myocardial fibrosis and edema in rheumatoid arthritis (RA) using multiparametric cardiac magnetic resonance (CMR) and the association of myocardial T1 and extracellular volume (ECV) with disease activity, duration, and cardiac function. BACKGROUND: RA is a connective tissue disorder, with frequent cardiovascular disease. Myocardial inflammation and diffuse fibrosis can be detected noninvasively by using native T1 mapping and ECV quantification on CMR. METHODS: Thirty-nine RA patients (28 women; mean age 50 ± 12 years) and 39 matched control subjects (28 women; mean age 49 ± 12 years) underwent CMR at 1.5-T, including cine, tagging, T2-weighted, native T1 mapping (shortened modified Look-Locker inversion recovery), late gadolinium enhancement (LGE), and ECV imaging. RESULTS: Focal fibrosis on LGE was found in 46% of RA patients compared with none of the control subjects. Patients with RA had larger areas of focal myocardial edema (10% vs. 0%), higher native T1 values (973 ± 27 ms vs. 961 ± 18 ms; p = 0.03), larger areas of involvement as detected by native T1 >990 ms (35% vs. 2%; p < 0.001), and expansion of ECV (30.3 ± 3.4% vs. 27.9 ± 2.0%; p < 0.001) compared with control subjects. Left ventricular volumes, mass, and ejection fraction were similar between RA patients and control subjects. Peak systolic circumferential strain (-16.9 ± 1.3 vs. -18.7 ± 1.2; p < 0.001) and peak diastolic circumferential strain rate (83 ± 21 s(-1) vs. 112 ± 20 s(-1); p < 0.001) were impaired in RA patients. Myocardial T1 and ECV were correlated with myocardial strain and RA disease activity. CONCLUSIONS: Subclinical cardiovascular disease is frequent in RA, including focal and diffuse myocardial fibrosis and inflammation, which are associated with impaired strain and RA disease activity. CMR T1 mapping provides potential added value as a biomarker for disease monitoring and study of therapies aimed at reducing diffuse myocardial fibrosis in RA.
25452308 Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synovi 2016 Feb OBJECTIVES: Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast-like synoviocytes (FLS). METHODS: Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays. RESULTS: Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class IIa HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1β or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1β, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1). CONCLUSIONS: Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment.
24532677 A genome-wide association study of rheumatoid arthritis without antibodies against citrull 2015 Mar INTRODUCTION: Rheumatoid arthritis (RA) patients can be classified based on presence or absence of anticitrullinated peptide antibodies (ACPA) in their serum. This heterogeneity among patients may reflect important biological differences underlying the disease process. To date, the majority of genetic studies have focused on the ACPA-positive group. Therefore, our goal was to analyse the genetic risk factors that contribute to ACPA-negative RA. METHODS: We performed a large-scale genome-wide association study (GWAS) in three Caucasian European cohorts comprising 1148 ACPA-negative RA patients and 6008 controls. All patients were screened using the Illumina Human Cyto-12 chip, and controls were genotyped using different genome-wide platforms. Population-independent analyses were carried out by means of logistic regression. Meta-analysis with previously published data was performed as follow-up for selected signals (reaching a total of 1922 ACPA-negative RA patients and 7087 controls). Imputation of classical HLA alleles, amino acid residues and single nucleotide polymorphisms was undertaken. RESULTS: The combined analysis of the studied cohorts resulted in identification of a peak of association in the HLA-region and several suggestive non-HLA associations. Meta-analysis with previous reports confirmed the association of the HLA region with this subset and an observed association in the CLYBL locus remained suggestive. The imputation and deep interrogation of the HLA region led to identification of a two amino acid model (HLA-B at position 9 and HLA-DRB1 at position 11) that accounted for the observed genome-wide associations in this region. CONCLUSIONS: Our study shed light on the influence of the HLA region in ACPA-negative RA and identified a suggestive risk locus for this condition.
27804999 Overexpression of soluble RAGE in mesenchymal stem cells enhances their immunoregulatory p 2016 Nov 2 Mesenchymal stem cells (MSCs) are attractive agents for cellular therapy in rheumatoid arthritis (RA). The receptor for advanced glycation end products (RAGE) serves as a pattern recognition receptor for endogenous inflammatory ligands. Soluble RAGE (sRAGE) is a truncated form of RAGE that functions as a decoy and acts as an anti-inflammatory molecule. The aim of this study was to determine whether sRAGE has therapeutic effects and the mechanisms active in sRAGE-overexpressing MSCs (sRAGE-MSCs) in an experimental model of RA. sRAGE-MSCs were generated by DNA transfection of human adipose tissue-derived MSCs (Ad-hMSCs). MSCs showed increased expression of VEGF, IL-1β, IL-6, and HMGB-1 under inflammatory conditions. However, sRAGE-MSCs showed significantly lower production of these proinflammatory molecules. Expression of immunomodulatory molecules such as IL-10, TGF-β, and indoleamine 2, 3-dioxygenase was higher in sRAGE-MSCs than in mock-MSCs. sRAGE-MSCs showed enhanced migration potential. Transplantation of sRAGE-MSCs into arthritic IL-1Ra-knockout mice markedly suppressed inflammatory arthritis, decreased Th17 cells, and reciprocally increased regulatory T cells. The differentiation of IFN-γ(+)CD4(+) and IL-17(+)CD4(+) cells was inhibited by incubation with sRAGE-MSCs compared with mock-MSCs. These findings suggest that sRAGE overexpression in Ad-hMSCs optimizes their immunoregulatory properties, which may be useful as a novel cellular therapy for RA.
27097684 Explanatory factors and predictors of fatigue in persons with rheumatoid arthritis: A long 2016 Apr 28 OBJECTIVE: To investigate the impact of disease-related aspects on long-term variations in fatigue in persons with rheumatoid arthritis. DESIGN: Observational longitudinal study. METHODS: Sixty-five persons with rheumatoid arthritis, age range 20-65 years, were invited to a clinical examination at 4 time-points during the 4 seasons. Outcome measures were: general fatigue rated on visual analogue scale (0-100) and aspects of fatigue assessed by the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire. Disease-related variables were: disease activity (erythrocyte sedimentation rate), pain threshold (pressure algometer), physical capacity (six-minute walk test), pain (visual analogue scale (0-100)), depressive mood (Hospital Anxiety and Depression scale, depression subscale), personal factors (age, sex, body mass index) and season. Multivariable regression analysis, linear mixed effects models were applied. RESULTS: The strongest explanatory factors for all fatigue outcomes, when recorded at the same time-point as fatigue, were pain threshold and depressive mood. Self-reported pain was an explanatory factor for physical aspects of fatigue and body mass index contributed to explaining the consequences of fatigue on everyday living. For predicting later fatigue pain threshold and depressive mood were the strongest predictors. CONCLUSION: Pain threshold and depressive mood were the most important factors for fatigue in persons with rheumatoid arthritis.
26021591 Arthritis at the shoulder joint. 2015 Jul The shoulder is a complex joint with numerous structures contributing to mobility and stability. Shoulder pain is a common clinical complaint that may be due to a wide spectrum of disorders including rotator cuff disease, instability, and arthropathy. Primary osteoarthritis of the shoulder joint is uncommon because it is a non-weight-bearing joint. Significant osteoarthritis of the glenohumeral joint is unusual in the absence of trauma, and the detection of advanced degenerative changes in patients without a known history of trauma should alert the clinician to search for other disorders. This article reviews the pathogenesis, clinical manifestations, and key imaging findings of the common categories of the arthritis affecting the glenohumeral joint.
25416067 Does the microbiota play a role in the pathogenesis of autoimmune diseases? 2015 Feb The microbiota of the human metaorganism is not a mere bystander. These microbes have coevolved with us and are pivotal to normal development and homoeostasis. Dysbiosis of the GI microbiota is associated with many disease susceptibilities, including obesity, malignancy, liver disease and GI pathology such as IBD. It is clear that there is direct and indirect crosstalk between this microbial community and host immune response. However, the precise mechanism of this microbial influence in disease pathogenesis remains elusive and is now a major research focus. There is emerging literature on the role of the microbiota in the pathogenesis of autoimmune disease, with clear and increasing evidence that changes in the microbiota are associated with some of these diseases. Examples include type 1 diabetes, coeliac disease and rheumatoid arthritis, and these contribute significantly to global morbidity and mortality. Understanding the role of the microbiota in autoimmune diseases may offer novel insight into factors that initiate and drive disease progression, stratify patient risk for complications and ultimately deliver new therapeutic strategies. This review summarises the current status on the role of the microbiota in autoimmune diseases.
26819496 Cyclic GMP-AMP Synthase Is Required for Cell Proliferation and Inflammatory Responses in R 2015 Rheumatoid arthritis (RA) is characterized by inflammatory cell infiltration, fibroblast-like synoviocytes (FLS) invasive proliferation, and joint destruction. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that induces immune activation. In this study, we examined whether cGAS plays a role in RA FLS. In this study, cGAS was overexpressed in RA-FLS compared with OA FLS. TNFα stimulation induced cGAS expression in RA FLS. Overexpression of cGAS promoted the proliferation and knockdown of cGAS inhibited the proliferation of RA FLS. cGAS overexpression enhanced the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) as well as AKT and ERK phosphorylation in TNFα-stimulated FLS. In contrast, cGAS silencing inhibited production of proinflammatory cytokines and matrix metalloproteinases (MMPs) as well as AKT and ERK phosphorylation in TNFα-stimulated FLS. These results suggest that cGAS activates the AKT and ERK pathways to promote the inflammatory response of RA FLS, and the development of strategies targeting cGAS may have therapeutic potential for human RA.