Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 34580414 | Direct tissue-sensing reprograms TLR4(+) Tfh-like cells inflammatory profile in the joints | 2021 Sep 27 | CD4(+) T cells mediate rheumatoid arthritis (RA) pathogenesis through both antibody-dependent and independent mechanisms. It remains unclear how synovial microenvironment impinges on CD4(+) T cells pathogenic functions. Here, we identified a TLR4(+) follicular helper T (Tfh) cell-like population present in the blood and expanded in synovial fluid. TLR4(+) T cells possess a two-pronged pathogenic activity whereby direct TLR4(+) engagement by endogenous ligands in the arthritic joint reprograms them from an IL-21 response, known to sponsor antibody production towards an IL-17 inflammatory program recognized to fuel tissue damage. Ex vivo, synovial fluid TLR4(+) T cells produced IL-17, but not IL-21. Blocking TLR4 signaling with a specific inhibitor impaired IL-17 production in response to synovial fluid recognition. Mechanistically, we unveiled that T-cell HLA-DR regulates their TLR4 expression. TLR4(+) T cells appear to uniquely reconcile an ability to promote systemic antibody production with a local synovial driven tissue damage program. | |
| 34920930 | Refractory CIDP successfully treated with autologous haematopoietic stem cell transplantat | 2022 Jan | Autologous haematopoietic stem cell transplantation is an emerging treatment option in refractory chronic inflammatory demyelinating polyradiculoneuropathy. We describe a case of a 46-year-old male, with history of IgG/lambda monoclonal gammopathy, who was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy at 27 years of age. After an initial 10-year period of corticotherapy response, the patient experienced severe relapses and disease progression, evolving to a refractory state. First-line and escalating treatment could not achieve clinical stabilization, leading to severe disability. Pre-treatment with ibrutinib was initiated and autologous haematopoietic stem cell transplantation was performed without significant complications. Marked clinical improvement was observed in the following months, both subjective and objective. A significant proportion of the patients who respond to the first-line immunosuppressive therapy eventually become treatment-refractory. Autologous haematopoietic stem cell transplantation may be a treatment option, offering long-term remission with an overall acceptable side effect and risk profile. | |
| 33752237 | Risk of venous thromboembolism associated with tofacitinib in patients with rheumatoid art | 2021 Dec 24 | OBJECTIVE: To evaluate the risk of venous thromboembolism (VTE) with tofacitinib compared with TNFis in patients with RA. METHODS: RA patients initiating tofacitinib or a TNFi without use of any biologic or tofacitinib any time prior were identified from IBM 'MarketScan' (2012-18), Medicare (parts A, B and D, 2012-17) or 'Optum' Clinformatics (2012-19) and followed until treatment discontinuation, treatment switch, insurance disenrollment or administrative censoring. The primary outcome, VTE, was identified using inpatient claims for pulmonary embolism or deep vein thrombosis. A Cox proportional hazards model provided hazard ratio (HR) and 95% CIs after accounting for confounding through propensity score fine-stratification weighting. HRs were pooled across databases with inverse variance meta-analytic method. RESULTS: A total of 42 201, 25 078 and 20 374 RA patients were identified from MarketScan, Medicare and Optum, respectively, of whom 7.1, 7.1 and 9.7% were tofacitinib initiators. The crude incidence rates per 100 person-years (95% CI) were 0.42 (0.20-0.77) and 0.35 (0.29-0.42) in MarketScan, 1.18 (0.68-1.92) and 0.83 (0.71-0.97) in Medicare, and 0.19 (0.04-0.57) and 0.34 (0.26-0.44) in Optum for tofacitinib and TNFis, respectively. Propensity score-weighted HRs showed no significant differences in the risk of VTE between tofacitinib and TNFis in any database with a pooled HR (95% CI) of 1.13 (0.77-1.65). CONCLUSION: Overall, VTE occurred infrequently (<1 per 100) in a total of 87 653 RA patients initiating tofacitinib or a TNFi. We observed no evidence for an increased risk of VTE for tofacitinib vs TNFis in RA patients. | |
| 33254235 | Safety and efficacy of fostamatinib in rheumatoid arthritis patients with an inadequate re | 2021 Jun 18 | OBJECTIVE: The primary objectives of two phase II studies of fostamatinib were to evaluate efficacy (OSKIRA-Asia-1: NCT01569074) and long-term safety/tolerability (OSKIRA-Asia-1X: NCT01640054) in patients from Asia with active RA despite MTX treatment. METHODS: OSKIRA-Asia-1 was a 12-week, multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive one of four fostamatinib doses (groups A-D; n = 31, 33, 33, 33) or placebo (group E; n = 33). OSKIRA-Asia-1X was a long-term extension study (100 mg fostamatinib qd) of patients who completed OSKIRA-Asia-1. RA signs and symptoms were measured by ACR response criteria and DAS based on a 28-joint count. Physical function status was assessed with the HAQ-Disability Index. Safety findings were monitored. RESULTS: In OSKIRA-Asia-1, fostamatinib revealed numerical improvements in ACR 20% response (ACR20) at week 12 in group A (100 mg bid) and group B (100 mg bid, then 150 mg qd) vs placebo. Statistically significant improvements in ACR20 and ACR50 at week 8 and in ACR70 at week 12, and statistically significant achievement in low disease activity (defined as DAS based on a 28-joint count ≤3.2 based on C-reactive protein) occurred in groups A and B. Improvement in physical function was numerically higher in group A. The most common adverse events were hypertension, diarrhoea and neutropenia. In OSKIRA-Asia-1X, the most common adverse events were nasopharyngitis, hypertension, RA and neutropenia. CONCLUSION: Fostamatinib achieved both statistically and clinically significant improvements in RA signs and symptoms. The safety and tolerability of fostamatinib (plus MTX) were consistent with previous studies. TRIAL REGISTRATION: OSKIRA-Asia-1 trial registration: https://clinicaltrials.gov, NCT01569074; OSKIRA-Asia-1X trial registration: https://clinicaltrials.gov, NCT01640054. | |
| 33038868 | Suppression of up-regulated LXRα by silybin ameliorates experimental rheumatoid arthritis | 2021 Jan | BACKGROUND: As dysregulation of immunometabolism plays a key role in the immunological diseases, dyslipidemia frequently observed in rheumatoid arthritis (RA) patients (60%) is associated with the disease activity and has been considered as the potential target of anti-inflammatory strategy. However, targeting of metabolic events to develop novel anti-inflammatory therapeutics are far from clear as well as the mechanism of dyslipidemia in RA. PURPOSE: To explore the therapeutic potential and mechanisms of silybin again RA through the regulation of lipid metabolism. METHODS: Adjuvant-induced arthritis (AIA) rat model was used to examine the effects of silybin on modulating dysregulated lipid metabolism and arthritis. Metabolomics, docking technology, and biochemical methods such as western blots, qRT-PCR, immunofluorescence staining were performed to understanding the underlying mechanisms. Moreover, knock-down of LXRα and LXRα agonist were used on LO2 cell lines to understand the action of silybin. RESULTS: We are the first to demonstrate that silybin can ameliorate dyslipidemia and arthritis in AIA rats. Overexpression of LXRα and several key lipogenic enzymes regulated by LXRα, including lipoprotein lipase (LPL), cholesterol 7α and 27α hydroxylase (CYP7A, CYP27A), adipocyte fatty acid-binding protein (aP2/FABP4) and fatty acid translocase (CD36/FAT), were observed in AIA rats, which mostly accounted for dyslipidemia during arthritis development. Metabolomics, docking technology, and biochemical results indicated that anti-arthritis effects of silybin related to suppressing the up-regulated LXRα and abnormal lipid metabolism. Notably, activation of LXRα could potentiate cell inflammatory process induced by LPS through the regulation of NF-κB pathway, however, suppression of LXRα agonism by siRNA or silybin reduced the nuclear translocation of NF-κB as well as the induction of downstream cytokines, indicating LXRα agonism is the important factor for the arthritis development and could be a potential target. CONCLUSION: The up-regulation of LXRα can activate lipogenesis enzymes to worsen the inflammatory process in AIA rats as well as the development of dyslipidemia, therefore, rectifying lipid disorder via suppression of LXRα agonism pertains the capacity of drug target, which enables to discover and develop new drugs to treat rheumatoid arthritis with dyslipidaemia. | |
| 33655915 | Efficacy and safety of Guizhi-Shaoyao-Zhimu decoction in the treatment of rheumatoid arthr | 2021 Mar 5 | BACKGROUND: Rheumatoid arthritis (RA) is a significant public health problem associated with a substantial burden of functional disability. The Guizhi-Shaoyao-Zhimu decoction (GSZD), a traditional medicine, has been used in China for a long time to treat RA. This study aimed to systematically investigate the efficacy and safety of GSZD in the treatment of RA. METHODS: We will search the electronic databases of PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, Wanfang Database, and China Biomedical Literature Database, and also manually search the Chinese Clinical Trial Register and unpublished studies or references, with the establishment up to February 2021. According to the inclusion and exclusion criteria, we will screen the literature, and the data are extracted independently by the 2 researchers. We will collect RCTs of GSZD in the treatment of RA. RevMan5.3 will be used for statistical analysis. According to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE), we will appraise each outcome quality evidence. RESULTS: We will publish the results in a peer-reviewed journal. CONCLUSION: We will evaluate the efficacy and safety of GSZD in treating RA. UNIQUE INPLASY NUMBER: INPLASY2020120147. | |
| 34291686 | Effects of Mild and Moderate Monoclonal Antibody Dose on Inflammation, Bone Loss, and Acti | 2021 Aug | Induction of severe inflammatory arthritis in the collagen antibody-induced arthritis (CAIA) murine model causes extensive joint damage and pain-like behavior compromising analysis. While mild models are less severe, their reduced, variable penetrance makes assessment of treatment efficacy difficult. This study aimed to compare macroscopic and microscopic changes in the paws, along with central nervous system activation between a mild and moderate CAIA model. Balb/c mice (n=18) were allocated to control, mild, and moderate CAIA groups. Paw inflammation, bone volume (BV), and paw volume (PV) were assessed. Histologically, the front paws were assessed for joint inflammation, cartilage damage, and pre/osteoclast-like cells and the lumbar spinal cord and the periaqueductal gray (PAG) region of the brain for glial reactivity. A moderate CAIA dose induced (1) significantly greater local paw inflammation, inflammatory cell infiltration, and PV; (2) significantly more osteoclast-like cells on the bone surface and within the surrounding soft tissue; and (3) significantly greater glial reactivity within the PAG compared with the mild CAIA model. These findings support the use of a moderate CAIA model (higher dose of monoclonal antibodies with low-dose lipopolysaccharide) to induce more consistent histopathological features, without excessive joint destruction. | |
| 34493490 | Analysing cord blood levels of TNF inhibitors to validate the EULAR points to consider for | 2022 Mar | BACKGROUND: To minimise placental transfer of tumour necrosis factor inhibitors (TNFi), the European League Against Rheumatism (EULAR) created points to consider (PtC) for the use of TNFi during pregnancy. We are the first to validate the EULAR-PtC by analysing TNFi concentrations in cord blood. METHODS: Patients were derived from the Preconceptional Counselling in Active Rheumatoid Arthritis Study. TNFi was stopped at the time points recommended by the EULAR. Maternal blood and cord blood were collected and analysed for the concentration of TNFi. RESULTS: 111 patients were eligible for the analysis. Median stop time points were gestational age (GA) 37.0 weeks for certolizumab pegol, GA 25.0 weeks for etanercept, GA 19.0 weeks for adalimumab and GA 18.4 weeks for infliximab. Certolizumab pegol (n=68) was detectable in 5.9% of cord blood samples, with a median concentration of 0.3 µg/mL (IQR: 0.2-1.3) and a median cord/maternal concentration ratio of 0.010. Etanercept (n=30) was not detected in any cord blood samples. Adalimumab (n=25) was detectable in 48.0% of cord blood samples, with a median concentration of 0.5 µg/mL (IQR: 0.2-0.7) and a median concentration ratio of 0.062 (IQR: 0.018-0.15). Infliximab (n=14) was detectable in 57.1% of cord blood samples, with a median concentration of 0.4 µg/mL (IQR: 0.1-1.2) and a median concentration ratio of 0.012 (IQR: 0.006-0.081). CONCLUSION: Compliance with the EULAR-PtC results in absence or low levels of TNFi in cord blood. | |
| 34275816 | Characterization and in vivo evaluation of nanoformulations in FCA induced rheumatoid arth | 2021 Mar | Rheumatoid arthritis is an inflammatory arthropathy, autoimmune in nature, leading to disability of joints involving structural destruction of articular bone and cartilage due to inflammation in synovium resulting in joint stiffness, swelling and pain. Nanomedicine has played a crucial role in improving the efficacy of treatment by controlling the release of pharmacologically active ingredients to increase bioavailability and achieve uniform and targeted delivery of drug. In this study, we prepared celecoxib, gingerol and oleanic acid loaded PLGA nanoparticles by solvent evaporation method and nanoparticles were characterized by particle size, zeta potential, polydispersity index, entrapement efficiency and FTIR. FCA is induced in right hand paw of rats for induction of arthritis. Celecoxib, gingerol and oleanic acid loaded PLGA nanoparticles coated with chitosan were given orally to rats for the evaluation of anti-arthritic effect of this nanoformulation in rats. Animals were divided into six groups for 21 days trial. On 21st day blood samples were collected for evaluation of hematological and lipid profile parameters. The data was subjected to statistical analysis by applying one way ANOVA and tukey test. At the end of study it was concluded that PLGA loaded celecoxib, gingerol and oleanic acid coated with chitosan have excellent effects in minimizing the side effects and increasing the therapeutic efficacy of drugs. | |
| 33083946 | Clinical profile and outcome of patients with chronic inflammatory arthritis and metabolic | 2021 Jun | Systemic chronic inflammation may favor the onset of metabolic syndrome (MetS) which represents a risk factor for CV events. Rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are disorders with high prevalence of MetS. We assessed the factors associated with MetS and its prognostic role in non-selected RA/AS/PsA patients. Between March 2014 and April 2016, 458 patients (228 RA, 134 PsA, 96 AS) selected for a primary prevention program for cardiovascular diseases were analyzed. Primary and co-primary end points were a composite of all-cause death/all-cause hospitalization and CV death/CV hospitalization, respectively. MetS was diagnosed according to the IDF Task Force on Epidemiology and Prevention. Patients were divided into MetS + (73 = 16%) and MetS - (385 = 84%). At multivariate logistic analysis, cancer, moderate/high disease activity, higher LV mass (LVM) and degree of LV diastolic dysfunction were independently associated with MetS. At 36-month follow-up, the event rate for primary/co-primary end point was 52/15% in MetS + vs 23/7% in MetS - (both p < 0.001). At multivariate Cox regression analysis, MetS was related to primary end point (HR 1.52 [CI 1.01-2.47], p = 0.04) together with higher LVM, disease duration and higher prevalence of biologic DMARDs refractoriness, and to co-primary end point (HR 2.05 [CI 1.16-3.60], p = 0.01) together with older age and higher LVM. The RA/AS/PsA phenotype MetS + is a subject with moderate/high disease activity, LV structural and functional abnormalities at increased risk for cancer. MetS + identifies RA/AS/PsA patients at higher risk for CV and non-CV events, independently of traditional CV risk factors analyzed individually and traditional indexes of inflammation. | |
| 33977741 | Patients with different types of arthritis may be at risk for major depression: results fr | 2021 May | BACKGROUND: Arthritis is one of the common causes of physical pain and disability, which often makes patients fall into major depression. However, the correlation between arthritis and major depression, and how different types of arthritis correspond to major depression remain to be explored. The purpose of this study is to explore the relationship between arthritis and major depression. METHODS: Arthritis status was reported by participants themselves, and the Patient Health Questionnaire-9 in National Health and Nutrition Examination Survey (NHANES) was used to evaluate major depression, logistic regression was used to evaluate the relationship between arthritis and major depression. RESULTS: We analyzed the data of 25,990 adults who participated in the NHANES from 2007 to 2018. Participants with major depression were more likely to be female, Hispanic, smoker, less educated, less recreational activities, poverty-to-income ratio <5, coronary heart disease, stroke, cancer or malignant tumor, diabetes, hypertension and higher body mass index (BMI). Arthritis was significantly correlated with major depression (25.4% vs. 44.9%; P<0.001), even after adjusting for gender, age, race, BMI, PIR, education, marriage, moderate recreational activities, smoking, history of coronary heart disease, stroke, cancer or malignant tumor, diabetes, and hypertension (OR =2.30, 95% CI, 2.06-2.56, P<0.001). Subgroup analysis showed that compared with degenerative arthritis, rheumatoid arthritis (RA), or other arthritis, psoriatic arthritis (PsA) had the greatest influence on major depression patients. CONCLUSIONS: All patients with arthritis, especially PsA, may have the risk of major depression. Psychological intervention necessary for patients with arthritis. | |
| 33347617 | CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macr | 2021 Apr | This study elucidates the mechanism of CCL25 and CCR9 in rheumatoid arthritis (RA). RA synovial fluid (SF) expresses elevated levels of CCL25 compared to OA SF and plasma from RA and normal. CCL25 was released into RA SF by fibroblasts (FLS) and macrophages (MΦs) stimulated with IL-1β and IL-6. CCR9 is also presented on IL-1β and IL-6 activated RA FLS and differentiated MΦs. Conversely, in RA PBMCs neither CCL25 nor CCR9 are impacted by 3-month longitudinal TNF inhibitor therapy. CCL25 amplifies RA FLS and monocyte infiltration via p38 and ERK phosphorylation. CCL25-stimulated RA FLS secrete potentiated levels of IL-8 which is disrupted by p38 and ERK inhibitors. CCL25 polarizes RA monocytes into nontraditional M1 MΦs that produce IL-8 and CCL2. Activation of p38 and ERK cascades are also responsible for the CCL25-induced M1 MΦ development. Unexpectedly, CCL25 was unable to polarize RA PBMCs into effector Th1/Th17 cells. Consistently, lymphokine like RANKL was uninvolved in CCL25-induced osteoclastogenesis; however, this manifestation was regulated by osteoclastic factors such as RANK, cathepsin K (CTSK), and TNF-α. In short, we reveal that CCL25/CCR9 manipulates RA FLS and MΦ migration and inflammatory phenotype in addition to osteoclast formation via p38 and ERK activation. | |
| 34347843 | Risk factor analysis of fragility fractures in rheumatoid arthritis: A 3-year longitudinal | 2021 | OBJECTIVES: To explore the risk factors for fragility fractures in rheumatoid arthritis (RA) patients using a 3-year longitudinal, observational cohort study. METHODS: This RA registry study included consecutive RA patients in the outpatient clinic of Chang Gung Memorial Hospital since September 1, 2014. The demographics, clinical characteristics, lifestyle, evidence of previous fracture, risk factors according to the Fracture Risk Assessment Tool (FRAX®), and the FRAX score of each participant were recorded. The participants were categorized into the new incident fracture (group A) and no incident fracture (group B) groups based on evidence or absence of new incident fractures and propensity score matching (age and gender, 1:2). RESULTS: Overall, 477 participants completed the 3-year observation period. After matching, 103 and 206 participants were allocated to groups A and B, respectively. The non-adjusted model revealed, presented as hazard ratio (HR) (95% confidence interval [CI]), that the presence of co-morbidity (1.80 [1.17-2.78], p = 0.008), Health Assessment Questionnaire Disability Index (1.35 [1.07-1.69], p = 0.010), lower baseline hip bone mineral density (0.11 [0.02-0.48], p = 0.004), longer disease duration (1.02 [1.00-1.04], p = 0.026), higher FRAX score of major fracture (1.03 [1.02-1.04], p<0.001) or hip fracture (1.03 [1.02-1.04], p<0.001), and previous fracture history (2.65 [1.79-3.94], p<0.001) were associated with new incident fracture. After adjustment, it was disclosed that a previous fracture is an independent risk factor for fragility fractures in RA patients (2.17 [1.20-3.90], p = 0.010). CONCLUSIONS: In addition to aging and disease-related factors, previous fracture history is the most important risk factor for fragility fractures in RA patients. | |
| 34691053 | Functionally Mature CD1c(+) Dendritic Cells Preferentially Accumulate in the Inflammatory | 2021 | OBJECTIVE: To examine the role of synovial CD1c(+)DCs in patients with Inflammatory Arthritis (IA) with a specific focus on the transcriptional and maturation signatures that govern their function. METHODS: RNA sequencing was performed on healthy control (HC) peripheral blood (PB), IA PB, and IA synovial fluid (SF) CD1c(+)DCs. Multiparametric flow-cytometry and SPICE analysis were used to examine site [SF and Synovial Tissue (ST) CD1c+DCs] and disease specific characteristics of CD1c(+)DCs, while functional assays such as antigen processing, activation, and MMP production were also performed. RESULTS: Increased frequency of CD1c(+)DCs (p<0.01) with a concomitant increase in CD80, CCR7 (p<0.01), and CXCR3 (p<0.05) expression was identified in IA PB compared to HC PB. Enrichment of CD1c(+)DCs was identified in IA synovial tissue (ST) (p<0.01) and IA SF (p<0.0001) compared to IA PB, while RNAseq revealed distinct transcriptional variation between PB and SF CD1c(+)DCs. Flow cytometry revealed increased expression of CD83, CD80, PD-L1, and BTLA (all p<0.05) in IA SF CD1c(+)DCs compared to PB, while SPICE identified synovial cells with unique co-expression patterns, expressing multiple DC maturation markers simultaneously. Functionally, synovial CD1c(+)DCs are hyper-responsive to TLR7/8 ligation (p<0.05), have decreased antigen processing capacity (p=0.07), and display dysregulated production of MMPs. Finally, examination of both synovial CD1c(+)DCs and synovial CD141(+)DCs revealed distinct maturation and transcriptomic profiles. CONCLUSION: Synovial CD1c(+)DCs accumulate in the inflamed IA synovium in a variety of distinct poly-maturational states, distinguishing them transcriptionally and functionally from CD1c(+)DCs in the periphery and synovial CD141(+)DCs. | |
| 33628802 | Serum IL-37 Level Is Associated with Rheumatoid Arthritis and Disease Activity: A Meta-Ana | 2021 | Interleukin-37 (IL-37) inhibits the pathogenesis of rheumatoid arthritis (RA) via downregulating proinflammatory cytokines. Accordingly, we performed an analysis to accurately assess the relationship between serum IL-37 cytokine levels and disease activity of RA. Subgroup analysis and sensitivity analysis were applied to explore the sources of heterogeneity. Correlation coefficient (r) was utilized to evaluate the relationship between IL-37 and disease activity of RA patients. Ten studies were included into the research. Functional analysis revealed elevated serum IL-37 concentrations in RA patients (SMD = 1.61, P < 0.00001). The relationship between serum IL-37 levels and disease activity was statistically significant (C-reactive protein: r = 1.47, P = 0.0002; erythrocyte sedimentation rate: r = 1.55, P < 0.00001; rheumatoid factor: r = 1.40, P = 0.004; tumor necrosis factorâƒÎ±: r = 1.64, P = 0.0003; Disease Activity Score for 28 joints: r = 1.63, P < 0.00001; tender joint count: r = 1.48, P < 0.00001; and swollen joint count: r = 1.52, P = 0.0003), but anti-CCP was not significant (anti-CCP: r = 0.98, P = 0.72). In summary, these data are suggesting that the elevated serum level of IL-37 in RA is positively correlated with the disease activity of RA, suggesting a role for IL-37in the pathogenesis of RA. | |
| 35000789 | Erosive arthritis autoantibodies in systemic sclerosis. | 2022 Feb | OBJECTIVE: We aimed to evaluate in two large SSc French cohorts the prevalence and associated factors with the autoantibodies linked to erosive arthritis. METHODS: 448 SSc patients were recruited from May 2015 to January 2019. Standardized clinical and laboratory variables were collected in accordance with the EUSTAR database. ELISAs for IgM rheumatoid factor (RF), IgG anti-citrullinated proteins (ACPA) and IgG anti-carbamylated proteins antibodies (anti-CarP) were all determined in a central laboratory. The prevalence and clinical associations of the different antibodies were investigated. RESULTS: RF positivity was observed in 113 patients (25%) compared to 39 (9%) for ACPA and 63 (14%) for anti-CarP antibodies. Through multivariate regression analysis, both RF and ACPA positivity resulted to be associated with RA overlap disease (OR 5.7, 95% CI 2.3-13.8 and OR 44.1, 95% CI 15.4-126.3, respectively). Additionally, ACPA was found to be significantly related to synovitis/ tenosynovitis (OR 1.7, 95% CI 1.0-2.6). RF positivity was associated to a "vascular subset" (i.e. any major vascular complication) (OR 2.1, 95% CI 1.3-3.4). Moreover, anti-CarP antibodies were associated with a fibrotic subset and with digital ulcers (OR 2.0, 95% CI 1.1-3.6 and OR 1.9, 95% CI 1.1-3.4). CONCLUSION: We corroborated that ACPA could be useful in identifying patients with a more prominent joint disease and RA overlap disease. Of the most interest we found that anti-CarP antibodies could be a relevant biomarker related to fibrotic skin and lung disease. | |
| 33740106 | Identification of Novel Pleiotropic SNPs Associated with Osteoporosis and Rheumatoid Arthr | 2021 Jul | Genome-wide association studies (GWASs) have identified hundreds of genetic loci for osteoporosis (OP) and rheumatoid arthritis (RA), individually, however, a large proportion of the total trait heritability remains unexplained. Previous studies demonstrated that these two diseases may share some common genetic determination and risk factors, but they were generally focused on individual trait and failed to identify the common variants that play key functional roles in the etiology of these two diseases. Here, we performed a conditional false discovery rate (cFDR) analysis to identify novel pleiotropic variants shared between them by integrating two independent GWASs with summary statistics for total body bone mineral density (TB-BMD, a major risk factor for osteoporosis) (n = 66,628) and RA (n = 58,284). A fine-mapping approach was also applied to identify the most probable causal variants with biological effects on both TB-BMD and RA. As a result, we found 47 independent pleiotropic SNPs shared between TB-BMD and RA, and 40 of them were validated in heel ultrasound estimated BMD (eBMD), femoral neck BMD (FN-BMD) or lumbar spine (LS-BMD). We detected one SNP (rs13299616) was novel and not identified by previous BMD or RA-related studies. Combined with fine-mapping and GWAS-eQTL colocalization analyses, our results suggested that locus 1p13.2 (including PTPN22, MAGI3, PHTF1, and RSBN1) was an important region to regulate TB-BMD and RA simultaneously. These findings provide new insights into the shared biological mechanisms and functional genetic determinants between OP and RA, and novel potential targets for treatment development. | |
| 32573417 | Inhibition of transient receptor potential canonical 6 attenuates fibroblast-like synovioc | 2021 Jan | OBJECTIVES: We aimed to define the importance of transient receptor potential canonical 6 (TRPC6) expression and function in fibroblast-like synoviocytes (FLSs) and to investigate the contribution of TRPC6 in the model of rheumatoid arthritis (RA). METHODS: We compared TRPC6 expression levels in FLSs from RA patients (RA-FLSs), and in FLSs from osteoarthritis (OA) patients (OA-FLSs). By using vitro functional assays which united with small interfering RNA-induced knockdown and functional modulation of TRPC6 in RA-FLSs. Finally, we confirmed the effectiveness of regulating TRPC6 in a collagen induced arthritis (CIA) mice model. RESULTS: We found that FLSs expressed the TRPC6 as their major Transient receptor potential canonical channel. Both mRNA and protein expression of TRPC6 were found somewhat higher levels in RA-FLSs than in OA-FLSs. Moreover, inhibiting expression of TRPC6 in vitro reduced proliferation of, as well as inflammatory mediator and protease production by, RA-FLSs, whereas opening native TRPC6 enhanced both proliferation and inflammatory mediator of RA-FLSs. Additionally, a TRPC6 deficiency in mice blunted the development of experimental RA, CIA models, reduced joint and bone damage, and inhibited FLS invasiveness and proliferation. CONCLUSIONS: Our results demonstrated a critical role of TRPC6 in regulating FLSs mediated inflammation. Therefore, TRPC6 represents potential therapeutic targets in RA. | |
| 32815449 | Three-year results of denosumab treatment for osteoporosis in women with rheumatoid arthri | 2021 May | INTRODUCTION: This study investigated the results of 3 years of denosumab treatment for osteoporosis in women with rheumatoid arthritis (RA) and primary osteoporosis (PO). MATERIALS AND METHODS: This study enrolled 112 women with RA (RA group) and 104 women with a PO group who received 60 mg denosumab for 3 years. Bone mineral densitiy (BMD) of the lumbar spine, total hip and femoral neck as well as levels of bone turnover markers [N-terminal propeptide of type I procollagen (P1NP) and tartrate-resistant acid phosphatase-5b (TRACP-5b)] were measured at years 1, 2, and 3. RESULTS: The percent changes (Δ) in BMD values at years 1, 2, and 3 were as follows: RA group: 6.7 ± 6.2%, 8.9 ± 6.5%, and 9.8 ± 8.2% and PO group: 6.0 ± 4.8%, 8.9 ± 7.5%, and 12.6 ± 8.7% for the lumbar spine; RA group: 4.5 ± 4.6%, 5.2 ± 5.1%, and 6.8 ± 5.9% and PO group: 3.8 ± 4.5%, 4.6 ± 7.4%, and 6.8 ± 4.6% for the total hip; and RA group: 2.7 ± 5.1%, 4.1 ± 6.8%, and 4.3 ± 6.7% and PO group: 3.6 ± 8.0%, 4.5 ± 10.9%, and 5.7 ± 10.5% for the femoral neck, respectively. The ΔBMD for the lumbar spine, total hip, and femoral neck as well as ΔP1NP and ΔTRACP-5b did not differ significantly between the two groups at any time points. CONCLUSION: Denosumab treatment for osteoporosis had a similar efficacy over 3 years among women with RA and PO. A better understanding of denosumab treatment for this patient population is important in clinical practice. | |
| 34751912 | Health-Care and Societal Costs Associated with Non-Persistence with Subcutaneous TNF-α In | 2022 Jun | OBJECTIVE: A few studies have suggested that patients with inflammatory arthritis (IA) who remain persistent with subcutaneous TNF-α inhibitors (SC-TNFi) incur lower health care costs than patients who discontinue treatment, whereas data on the impact of non-persistence on indirect costs are largely lacking. Furthermore, existing estimates are based on fixed follow-ups, in relation to treatment initiation, and therefore do not measure costs in direct relation to treatment discontinuation. Therefore, by capturing costs in direct relation to treatment discontinuation, this study aimed to estimate direct and indirect costs associated with non-persistence with SC-TNFis in IA. METHODS: Adult Swedish biologic-naïve IA patients initiating biologic treatment with a SC-TNFi (adalimumab, etanercept, certolizumab or golimumab) between May 6, 2010, and December 31, 2017, were identified in population-based registers with almost complete coverage. IA was defined as a diagnosis of rheumatic arthritis, ankylosing spondylitis/unspecified spondyloarthritis or psoriatic arthritis. Non-persistent patients were matched on propensity score to patients persistent with treatment by at least an additional 12 months. This enabled comparisons of direct healthcare costs and indirect costs for sick leave and disability pension, respectively, 12 months before and 12 months after treatment discontinuation. RESULTS: A balanced cohort of 486 matched pairs was generated. The total direct and indirect costs were significantly higher among non-persistent patients already during the 12 months before index ($20,802 [18,335-23,429] vs. $16,600 [14,331-18,696]). However, while non-persistent patients increased their total direct and indirect costs, persistent patients significantly decreased the same, further widening the difference in costs during the 12-month period after index date ($22,161 [19,754-24,556] vs. $13,465 [11,415-15,729]). CONCLUSIONS: Among biologic-naïve Swedish IA patients treated with SC-TNFis, persistent patients incurred about 40% lower aggregated direct and indirect costs compared to non-persistent patients the year following SC-TNFi discontinuation. This highlights the impact of treatment persistence from an economic viewpoint, adding further aspects to the clinical perspective. |