Lesions In Rheumatoid Arthritis Research Articles

Microenvironment-Activatable Probe for Precise NIR-II Monitoring and Synergistic Immunotherapy in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) represents an insidious autoimmune inflammatory disorder that severely lowers the life quality by progressively destructing joint functions and eventually causing permanent disability, posing a serious public health problem. Here, an advanced theranostic probe is introduced that integrates activatable second near-infrared (NIR-II) fluorescence imaging for precise RA diagnosis with multi-pronged RA treatments. A novel molecular probe comprising a long-wavelength aggregation-induced emission unit and a manganese carbonyl cage motif is synthesized, which enables NIR-II fluorescence activation and concurrently releasing therapeutic carbon monoxide (CO) gas in inflamed joint microenvironment. This molecular probe self-assembles into a biocompatible nanoprobe, which is subsequently conjugated with anti-IL-6R antibody to afford active-targeting ability of RA. The nanoprobe exhibits significant turn-on NIR-II fluorescence signal at the RA lesion, enabling highly sensitive RA diagnosis and real-time therapeutic monitoring. The combination of ROS scavenging, on-demand CO gas release, and IL-6 signaling blockade results in potent therapeutic effect and synergistic immunomodulation impact, significantly alleviating the RA symptoms and preventing joint destruction. This research introduces a novel paradigm for the development of high-performance, activatable theranostic strategies to facilitate precise detection and enhanced treatment of RA-related diseases.

Rheumatoid meningitis sine arthritis: An emerging cause of isolated pachymeningitis and leptomeningitis with typical features

Background and purposeRheumatoid meningitis (RM) is a meningeal inflammation rarely occurring during the course of rheumatoid arthritis (RA). Anti-citrullinated protein antibodies (ACPA), which are highly specific biomarkers of RA, may allow RM sine arthritis (RMSA) to be diagnosed as an extra-articular early lesion of RA. MRI typically displays pachymeningitis and/or leptomeningitis predating convexity, and CSF diffusivity is focally restricted. Blood ACPA is a strong clue and intrathecal synthesis of ACPA is characteristic although rarely reported. MethodsWe report two cases of RMSA that were confirmed by meningeal biopsy and intrathecal synthesis. ResultsRMSA abated after steroids alone or associated with rituximab. No arthritis occurred during the follow-up. ConclusionRM can occur in the absence of RA.

Apoptotic extracellular vesicles restore homeostasis of the articular microenvironment for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a severe autoimmune disease with symptoms including synovial inflammation, cartilage erosion, and bone loss in RA lesions, which eventually lead to joint deformity and function loss. Most current treatments fail to achieve satisfying therapeutic outcomes with some adverse effects. Extracellular vesicles derived from apoptotic cells (apoEVs) have emerged as important mediators in intercellular communication regulating diverse physiological and pathological processes. In this study, we investigated the therapeutic efficacy of macrophage-derived and osteoclast-derived apoEVs (Mφ-apoEVs and OC-apoEVs) on RA. The in vitro results showed that both Mφ-apoEVs and OC-apoEVs induced macrophage repolarization toward the anti-inflammatory M2 phenotype, promoted chondrocyte functions and chondrogenesis, and inhibited osteoclast formation and maturation. In addition, OC-apoEVs promoted osteogenic differentiation. The in vivo study on the CIA mouse model further demonstrated that apoEVs could couple various functions and exert synergistic effects on the joint with RA, as evidenced by the regression of synovial inflammation, the reversal of cartilage damage and bone erosion, and the preservation of joint structure. These findings demonstrated that Mφ-apoEVs and OC-apoEVs contributed to restoring the homeostasis of the overall microenvironment in the RA joint and highlighted their potential application as a promising alternative to treat RA.

The effect of long-term traditional Chinese medicine treatment on extra-articular lesions of rheumatoid arthritis patients based on propensity score matching: A retrospective cohort study

ObjectiveTo explore the efficacy of long-term traditional Chinese medicine (TCM) treatment on the occurrence of extra-articular lesions in rheumatoid arthritis (RA) patients. MethodsOur retrospective cohort study included patients diagnosed with RA between January 2018 to December 2019. Patients were divided into TCM treatment group and control group according to whether they received TCM treatment for more than three months. Propensity score matching (PSM) was used to balance covariates between groups. The occurrence time of extra-articular lesions, including interstitial lung disease, Sjögren's syndrome, and anemia, was calculated for both groups after PSM. Additionally, clinical indicators that may affect the occurrence of extra-articular lesions in RA were included in Cox multivariate regression analysis to explore prognostic factors related to RA. ResultsA total of 883 RA patients were initially included in our study, with 481 in the TCM treatment group and 279 in the control group. TCM treatment improved all clinical indicators of RA patients, and there was a higher degree of support, confidence, and lift between TCM treatment and the improvement of clinical indicators. There was no significant difference in the rate of extra-articular lesions occurrence between the two groups. After PSM, the median occurrence time of interstitial lung disease, Sjögren's syndrome and anemia in the TCM treatment group were 30.767, 21.370 and 31.970 months, respectively. While in the control group, it was 15.911, 14.667 and 11.825 months, respectively. Cox multivariate regression analysis indicated that TCM treatment was a protective factor for the occurrence of extra-articular lesions in RA, while abnormally high level of IgG was an independent factor for interstitial lung disease and C4 was an independent factor for Sjögren's syndrome. Moreover, a longer duration of TCM usage was associated with a later occurrence of extra-articular lesions. ConclusionLong-term TCM treatment not only positively affects the occurrence time of extra-articular lesions in RA patients, but also helps reduce the risk of extra-articular lesions occurrence. TCM can be applied flexibly throughout the treatment process for RA patients.

Value of Magnetic Resonance T1 Mapping in Evaluating the Early Response to Treatment for Rheumatoid Arthritis.

Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) is usually used for the semi-quantitative evaluation of joint changes in Rheumatoid Arthritis (RA). However, this method cannot evaluate early changes in bone marrow edema (BME). To determine whether T1 mapping of wrist BME predicts early treatment response in RA. This study prospectively enrolled 48 RA patients administered oral anti-rheumatic drugs. MRI of the most severely affected wrist was performed before and after 4 (48 patients) and 8 weeks of treatment (38 patients). Mean T1 values of BME in the lunate, triangular, and capitate bones; RAMRIS for each wrist; Erythrocyte-Sedimentation Rate (ESR); and 28-joint Disease Activity Score (DAS28)-ESR score were analyzed. Patients were divided into responders (4 weeks, 30 patients; 8 weeks, 32 patients) and non-responders (4 weeks, 18 patients; 8 weeks, 6 patients), according to EULAR response criteria. Receiver operating characteristic (ROC) curves were used to evaluate the efficacy of T1 values. ESR and DAS28-ESR were not correlated with T1 value and RAMRIS at each examination (P > 0.05). Changes in T1 value and DAS28-ESR relative to the baseline were moderately positively correlated with each other at 4 and 8 weeks (r = 0.555 and 0.527, respectively; P < 0.05). At 4 weeks, the change and rate of change in T1 value significantly differed between responders and non-responders (-85.63 vs. -19.92 ms; -12.89% vs. -2.81%; P < 0.05). The optimal threshold of the rate of change in T1 value at 4 weeks for predicting treatment response was -5.32% (area under the ROC curve, 0.833; sensitivity, 0.900; specificity, 0.667). T1 mapping provides a new imaging method for monitoring RA lesions; changes in wrist BME T1 values reflect early treatment response.

Proteomics analysis of lung tissue reveals protein makers for the lung injury of adjuvant arthritis rats.

Lung injury is one of the common extra‑articular lesions in rheumatoid arthritis (RA). Due to its insidious onset and no obvious clinical symptoms, it can be easily dismissed in the early stage of diagnosis, which is one of the reasons that leads to a decline of the quality of life and subsequent death of patients with RA. However, its pathogenesis is still unclear and there is a lack of effective therapeutic targets. In the present study, tandem mass tag‑labeled proteomics was used to research the lung tissue proteins in RA model (adjuvant arthritis, AA) rats that had secondary lung injury. The aim of the present study was to identify the differentially expressed proteins related to RA‑lung injury, determine their potential role in the pathogenesis of RA‑lung injury and provide potential targets for clinical treatment. Lung tissue samples were collected from AA‑lung injury and normal rats. The differentially expressed proteins (DEPs) were identified by tandem mass spectrometry. Bioinformatic analysis was used to assess the biological processes and signaling pathways associated with these DEPs. A total of 310 DEPs were found, of which 244 were upregulated and 66 were downregulated. KEGG anlysis showed that 'fatty acid degradation', 'fatty acid metabolism', 'fatty acid elongation', 'complement and coagulation cascades', 'peroxisome proliferator‑activated receptor signaling pathway' and 'hypoxia‑inducible factor signaling pathway' were significantly upregulated in the lung tissues of AA‑lung injury. Immunofluorescence staining confirmed the increased expression of clusterin, serine protease inhibitors and complement 1qc in lung tissue of rats with AA lung injury. In the present study, the results revealed the significance of certain DEPs (for example, C9, C1qc and Clu) in the occurrence and development of RA‑lung injury and provided support through experiments to identify potential biomarkers for the early diagnosis and prevention of RA‑lung injury.

Multifunctional Janus Nanoplatform for Efficiently Synergistic Theranostics of Rheumatoid Arthritis

Progress has been made in the application of nanomedicine in rheumatoid arthritis (RA) treatment. However, the whole process of monitoring and treatment of RA remains a formidable challenge due to the complexity of the chronic autoimmune disease. In this study, we develop a Janus nanoplatform (denoted as Janus-CPS) composed of CeO2-Pt nanozyme subunit on one side and periodic mesoporous organosilica (PMO) subunit on another side for simultaneous early diagnosis and synergistic therapy of RA. The Janus nanostructure, which enables more active sites to be exposed, enhances the reactive oxygen species scavenging capability of CeO2-Pt nanozyme subunit as compared to their core-shell counterpart. Furthermore, micheliolide (MCL), an extracted compound from natural plants with anti-osteoclastogenesis effects, is loaded into the mesopores of PMO subunit to synergize with the anti-inflammation effect of nanozymes for efficient RA treatment, which has been demonstrated by in vitro cellular experiments and in vivo collagen-induced arthritis (CIA) model. In addition, by taking advantage of the second near-infrared window (NIR-II) fluorescent imaging, indocyanine green (ICG)-loaded Janus-CPS exhibits desirable effectiveness in detecting RA lesions at a very early stage. It is anticipated that such a Janus nanoplatform may offer an alternative strategy of functional integration for versatile theranostics.

Are Viral Infections Key Inducers of Autoimmune Diseases? Focus on Epstein-Barr Virus.

It is generally accepted that certain viral infections can trigger the development of autoimmune diseases. However, the exact mechanisms by which these viruses induce autoimmunity are still not understood. In this review, we first describe hypothetical mechanisms by which viruses induce some representative autoimmune diseases. Then, we focus on Epstein–Barr virus (EBV) and discuss its role in the pathogenesis of rheumatoid arthritis (RA). The discussion is mainly based on our own previous findings that (A) EBV DNA and its products EBV-encoded small RNA (EBER) and latent membrane protein 1 (LMP1) are present in the synovial lesions of RA, (B) mRNA expression of the signaling lymphocytic activation molecule-associated protein (SAP)/SH2D1A gene that plays a critical role in cellular immune responses to EBV is reduced in the peripheral T cells of patients with RA, and (C) EBV infection of mice reconstituted with human immune system components (humanized mice) induced erosive arthritis that is pathologically similar to RA. Additionally, environmental factors may contribute to EBV reactivation as follows: Porphyromonas gingivalis peptidylarginine deiminase (PAD), an enzyme required for citrullination, engenders antigens leading to the production of citrullinated peptides both in the gingiva and synovium. Anti-citrullinated peptides autoantibody is an important marker for diagnosis and disease activity of RA. These findings, as well as various results obtained by other researchers, strongly suggest that EBV is directly involved in the pathogenesis of RA, a typical autoimmune disease.

Development of pH-sensitive dextran-based methotrexate nanodrug for rheumatoid arthritis therapy through inhibition of JAK-STAT pathways

Rheumatoid arthritis (RA) is a chronic and symmetrical autoimmune disease that primarily characterized with articular synovial hyperplasia, joint swelling, cartilage and bone destruction. The in-depth understanding of the role of immune signaling pathway inhibitors provides inspiration for the construction of new and more effective strategy for RA therapy. In this study, by loading methotrexate (MTX) into an acetalated dextran biopolymer, AcDEX, we developed a pH-sensitive, MTX-loaded and molecularly targeted nanodrug MTX@pH-AcDEX NPs) to decrease the toxicity of MTX and simultaneously enhance its therapeutic effect. The resultant MTX@pH-AcDEX NPs showed the spherical morphology and notable pH-responsiveness with high drug loading of 88.32%. As demonstrated in vitro and in vivo, the reduced cytotoxicity of both RAW264.7 cells and LPS-activated RAW264.7 cells treated with MTX@pH-AcDEX NPs was found compared to free MTX. Upon intravenous administration into adjuvant-induced arthritis (AIA) rat model, the nanodrug had potent pharmacokinetic and pharmacodynamic profiles, which can accumulate in RA lesions and release MTX inhibitors for regulating the JAK-STAT pathways. As a result, the MTX@pH-AcDEX NPs achieved the cartilage and bone protective and a better anti-inflammatory effect with negligible systemic toxicity, suggesting the strong potential of safe and effective nanodrug for RA therapy as well as other autoimmune diseases.

Rheumatoid Arthritis: An Examination of Arthropathy in Antiquity

Arthropathy – or joint disease – is the most common post-cranial pathological change found in skeletal remains, both today and in the past. Responsible for a great amount of pain and discomfort in modern populations, arthropathy continues to be highly researched in current clinical and pale­opathological studies. Despite its frequency in an archaeological context, differentiation between various types of arthropathy can prove challenging. Rheumatoid arthritis (RA), for example, is historically underrepresented in the archaeological record. This may be due to a combination of the poor preservation of hand and foot bones (the locale where the bony alterations of RA begin), the non-specific appearance of RA lesions on bones, as well as other biases inherent in the bioar­cheological record. This article analyzes the origins and antiquity of RA, as well as some of the issues with differential diagnosis using clinical and paleopathological literature, including proba­ble and potential cases.

Incidence of and risk factors for spondylolisthesis, scoliosis, and vertebral fracture in rheumatoid arthritis.

Although lumbar lesions such as spondylolisthesis, scoliosis, and vertebral fracture are not specific to rheumatoid arthritis (RA), the prevalence is high in RA patients. However, no longitudinal study has evaluated lumbar lesions in RA. This study aimed to investigate the incidence of and risk factors for lumbar lesions in RA by a prospective longitudinal cohort study. The study cohort comprised 110 patients with RA from the 'analysis of factors for RA spinal disorders (AFFORD)' study who completed the secondary survey at a single orthopaedic outpatient RA clinic. Radiological examination included standing radiographs and magnetic resonance imaging (MRI) of the lumbar spine. New development of spondylolisthesis, scoliosis, and vertebral fracture were assessed between baseline and secondary survey. The incidences of spondylolisthesis, scoliosis, and vertebral fracture were 42%, 16%, and 12%, respectively, during a mean follow-up of 7years. The independent risk factor for de novo scoliosis was poor control of RA (adjusted odds ratio [aOR] 4.81, p = 0.011), while the independent risk factors for new vertebral fracture was use of glucocorticoid at secondary survey (aOR 14.87, p = 0.012). Patients with de novo scoliosis exhibited more severe low back pain and lower quality of life than those without. The incidence of scoliosis was related in patients with poor control of RA, while new vertebral fracture was more common in patients with use of glucocorticoid. Control of disease activity might be important in preventing radiological lumbar disorders in RA.

Paramagnetic block copolymers: An effective tool for targeted radiography of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by erosive arthritis. Accurate diagnosis of RA mostly depends on the quality of magnetic resonance imaging (MRI). To obtain stable and clear imaging signals, it is necessary to design and develop a superstable and highly sensitive contrast agent. This study synthesized a diblock polymer polyethylene glycol–tert-butyl polyacrylate (PEG-b-PAA) by in situ polyol polymerization, coated it with ultrasmall paramagnetic iron oxide (USPIO), and conjugated folic acid to the PEG-b-PAA/USPIO surface to impart targeting function. The addition of USPIO effectively enhanced MRI quality in delayed T2-weighted images (T2WI), as observed through synovial signal changes other than morphological changes, early monitoring RA lesions, and drug treatment response. Enhanced T2WI helped evaluate the characteristics of synovial perfusion, which further confirmed the feasibility of MRI using FA-PEG-b-PAA/USPIO. These results showed that FA-PEG-b-PAA/USPIO has great potential in the clinical application of MRI for RA diagnosis.

Identification of Disease-Specific Hub Biomarkers and Immune Infiltration in Osteoarthritis and Rheumatoid Arthritis Synovial Tissues by Bioinformatics Analysis.

Background Osteoarthritis (OA) and rheumatoid arthritis (RA) are well-known cause of joint disability. Although they have shown the analogous clinical features involving chronic synovitis that progresses to cartilage and bone destruction, the pathogenesis that initiates and perpetuates synovial lesions between RA and OA remains elusive. Objective This study is aimed at identifying disease-specific hub genes, exploring immune cell infiltration, and elucidating the underlying mechanisms associated with RA and OA synovial lesion. Methods Gene expression profiles (GSE55235, GSE55457, GSE55584, and GSE12021) were selected from Gene Expression Omnibus for analysis. Differentially expressed genes (DEGs) were identified by the “LIMMA” package in Bioconductor. The DEGs were identified by Gene Ontology (GO) and KEGG pathway analysis. A protein-protein interaction network was constructed to identify candidate hub genes by using STRING and Cytoscape. Hub genes were identified by validating from GSE12021. Furthermore, we employed the CIBERSORT website to assess immune cell infiltration between OA and RA. Finally, we explored the correlation between the levels of hub genes and relative proportion of immune cells in OA and RA. Results We identified 68 DEGs which were mainly enriched in immune response and chemokine signaling pathway. Six hub genes with a cutoff of AUC > 0.80 by ROC analysis and relative expression of P < 0.05 were identified successfully. Compared with OA, the RA synovial tissues consisted of a higher proportion of 7 immune cells, whereas 4 immune cells were found in relatively lower proportion (P < 0.05). In addition, the levels of 6 hub genes were closely associated with relative proportion of 11 immune cells in OA and RA. Conclusions We used bioinformatics analysis to identify hub genes and explored immune cell infiltration of immune microenvironment in synovial tissues. Our results should offer insights into the underlying molecular mechanisms of synovial lesion and provide potential target for immune-based therapies of OA and RA.

NIR-Responsive Spatiotemporally Controlled Cyanobacteria Micro-Nanodevice for Intensity-Modulated Chemotherapeutics in Rheumatoid Arthritis.

The expression of hypoxia-inducible factor-1α (HIF-1α) is upregulated in hypoxic environments at the lesions of rheumatoid arthritis (RA), which promoted the polarization of proinflammatory M1 macrophages and inhibited the differentiation of anti-inflammatory M2 to deteriorate synovial inflammation. Since oxygen scarcity at the joints causes an imbalance of macrophages M1 and M2, herein, we designed a cyanobacteria micro-nanodevice that can be spatiotemporally controlled in vivo to continuously producing oxygen in the RA joints for the downregulation of the expression of HIF-1α, thereby reducing the amounts of M1 macrophages and inducing the polarization of M2 macrophages for chemically sensitized RA treatment. The forthputting of temperature-sensitive hydrogel guaranteed the safety of cyanobacteria micro-nanodevice in vivo. Furthermore, the oxygen produced by cyanobacteria micro-nanodevice in a sustained manner enhanced the therapeutic effect of the antirheumatic drug methotrexate (MTX) and discouraged inflammation and bone erosion at RA. This study provided a new approach for the RA treatment of spatiotemporal-controlled release of oxygen in vitro.

Protective Effect of Tangeretin and 5-Hydroxy-6,7,8,3',4'-Pentamethoxyflavone on Collagen-Induced Arthritis by Inhibiting Autophagy via Activation of the ROS-AKT/mTOR Signaling Pathway.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by long duration and repeated relapse. This study explored the preventive effect of tangeretin (TAN) and 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone (5-HPMF) on RA, and the underlying molecular mechanism based on a rat model stimulated by bovine type II collagen (BIIC). After the intervention of TAN or 5-HPMF (TAN/5-HPMF) for 5 weeks, the RA lesions and autophagy levels of the synovial tissue were significantly reduced, and the ROS content and HO-1 expression level were down-regulated simultaneously. The relative expression levels of p-AKT and p-mTOR were down-regulated after TAN/5-HPMF feeding. Meanwhile, the relative expression level of p62 increased by more than two-fold for TAN/5-HPMF treated rats at 200 mg/kg BW comparing with those in BIIC group. Results of immunofluorescence staining and Western blotting further confirmed that TAN/5-HPMF treatment reduced BIIC-induced conversion from LC3I to LC3II. Observations under transmission electron microscope also demonstrated that the autophagy level was reduced upon TAN/5-HPMF intervention. Collectively, these results revealed that TAN and 5-HPMF prevented the pathological process of BIIC-stimulated arthritis through inhibiting the autophagy of synovial cells, achieved via the ROS-AKT/mTOR signal axis. Thus, our findings confirmed the protective potential of TAN and 5-HPMF for RA disease.

Targeted Combination of Antioxidative and Anti-Inflammatory Therapy of Rheumatoid Arthritis using Multifunctional Dendrimer-Entrapped Gold Nanoparticles as a Platform.

Abundant reactive oxygen species and tumor necrosis factor-α (TNF-α) cytokine supply of M1-type macrophages boost rheumatoid arthritis (RA) pathological process. For efficient RA therapy, here a multifunctional nanoplatform is presented based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to achieve co-delivery of antioxidant alpha-tocopheryl succinate (α-TOS) and anti-inflammatory anti-TNF-α siRNA to macrophage cells. G5 dendrimers with amine termini are sequentially functionalized with 1,3-propane sultone (1,3-PS), α-TOS through a polyethylene glycol (PEG) spacer, and PEGylated folic acid (FA), and subsequently entrapped with Au NPs. The generated functional Au DENPs exhibit desired cytocompatibility, zwitterion-rendered antifouling property, and FA-mediated targeting specificity, enabling serum-enhanced siRNA delivery to M1-type macrophage cells. Meanwhile, the attached α-TOS affords enhanced oxidation resistance of macrophage cells. In vivo investigation shows that the treatment of a collagen-induced arthritis mouse model using α-TOS-modified Au DENPs/TNF-α siRNA polyplexes can achieve excellent combination therapy effect in inflammatory cytokines downregulation of RA lesion and bone erosions. The therapeutic efficacy is also supported by 3D micro-computed tomography analysis and TNF-α cytokine reduction of RA lesion joints in the mRNA, protein, and histology levels. The created multifunctional nanoplatform may be employed in antioxidative and anti-inflammatory combination therapy of RA.

Change of ARASHI scores for large joints in rheumatoid arthritis patients treated with abatacept for three years: A clinical observational study.

Objectives This study aims to investigate large joint damage progression using the assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging (ARASHI) score in patients with rheumatoid arthritis (RA) treated with abatacept for three years.Patients and methods A total of 71 consecutive patients with RA (7 males, 64 females; median age 68 years; range, 41 to 81 years) and joint lesions (141 shoulders, 139 elbows, 141 hips, 134 knees, and 142 ankles) treated with abatacept for three years were examined. Radiographic changes were assessed using the ARASHI score, and factors associated with radiographic progressive damage of large joints were analyzed using multivariate logistic regression.Results The three-year radiographic progressive damage rates for the upper and lower limb large joints were 18.3% and 22.5%, respectively. Rates for the shoulder and knee decreased significantly (p=0.025 and 0.039, respectively), whereas rate for the ankle increased significantly (p=0.043). Multivariate logistic regression analysis identified the baseline ARASHI status score as an independent predictor of progressive damage of upper limb large joints within three years (p=0.004; odds ratio, 1.17). The cutoff value of the ARASHI status score for the upper limb large joints was 4, as determined from the receiver operating characteristics curve. No significant predictors of progressive damage were identified in the lower limb large joints within three years.ConclusionThe greatest suppression of the radiographic progressive damage of large joints was achieved for the shoulders and knees. Meanwhile, ankle damage progressed. Therefore, ankle joint damage should be monitored even in patients treated with abatacept. In the upper limbs, prescribing abatacept to patients with RA depending on their state of upper limb large joint damage may suppress damage progression.

THU0132 ASSOCIATION OF RHEUMATOID ARTHRITIS AND DEMENTIA: A NATIONWIDE POPULATION-BASED STUDY

Background: Cumulative inflammation correlates with coronary plaque increase and cardiovascular disease (CVD) events in rheumatoid arthritis (RA). Coronary plaque progression predicts CVD risk beyond baseline burden in general patients. Statins inhibit plaque progression and are effective for CVD prevention in general patients. Nevertheless, their impact on coronary plaque trajectory and CVD risk in RA are less clear. Objectives: To explore if statin treatment may reduce CVD event risk, inhibit new plaque formation or promote the regression or protective calcification of prevalent atherosclerotic lesions in RA. We also evaluated whether statins moderate the effects of inflammation (CRP) on CVD risk and on coronary plaque progression. Methods: One hundred-fifty patients underwent computed tomography angiography for coronary atherosclerosis evaluation (total, non-calcified, mixed/calcified plaque); 101 had repeat assessments within 6.9±0.3 years to evaluate plaque progression. CVD events were prospectively recorded, including cardiac death, myocardial infarction, unstable angina, revascularization, stroke, claudication, and heart failure hospitalization. Framingham-D’Agostino score assessed clinical risk. Plaque burden was measured as segment stenosis score (cumulative stenosis). Robust cox proportional hazards regression models evaluated the effects of time-varying statin use, log-transformed time-varying CRP (mg/dL) and their interaction on CVD risk controlling for Framingham-D’Agostino score, plaque burden and time-varying bDMARD use. Per-segment robust logistic regression assessed the effect of statin duration (years), log-transformed time-averaged CRP, and their interaction on likelihood of plaque formation in segments without plaque, and plaque regression or calcification in segments with non-calcified lesions. Models accounted for clustering of coronary segments within patients and controlled for Framingham-D’Agostino score, total prednisone dose, bDMARD duration, and time between scans. Results: Sixteen patients incurred 19 CVD events. There was no main effect of current statin use on CVD risk (adjusted HR 1.10, 95% CI 0.33-3.67). However, there was an interaction between current statin use and time-varying CRP (p-interaction=0.030); higher time-varying CRP predicted greater CVD risk in patients not receiving statins (adjusted HR 2.78, 95% CI 1.01-7.65), but not current statin users (Figure 1A). Likewise, current statin use associated with lower CVD risk when patients had higher time-varying CRP (>0.5 mg/dL) but not when CRP was lower ( Conclusion: In RA, statins moderated the effect of CRP on CVD event risk and new plaque formation in coronary segments without plaque. Longer statin duration was also associated with an increased likelihood of protective calcification of non-calcified plaque. Disclosure of Interests: George Karpouzas Grant/research support from: Pfizer, Consultant of: Sanofi-Genzyme-Regeneron, Janssen, Speakers bureau: Sanofi-Genzyme-Regeneron, BMS, Sarah Ormseth: None declared, Elizabeth Hernandez: None declared, Matthew Budoff: None declared

THU0139 STATINS MODERATE THE EFFECT OF INFLAMMATION ON CORONARY PLAQUE PROGRESSION AND CARDIOVASCULAR DISEASE RISK IN RHEUMATOID ARTHRITIS

Background:Cumulative inflammation correlates with coronary plaque increase and cardiovascular disease (CVD) events in rheumatoid arthritis (RA). Coronary plaque progression predicts CVD risk beyond baseline burden in general patients. Statins inhibit plaque progression and are effective for CVD prevention in general patients. Nevertheless, their impact on coronary plaque trajectory and CVD risk in RA are less clear.Objectives:To explore if statin treatment may reduce CVD event risk, inhibit new plaque formation or promote the regression or protective calcification of prevalent atherosclerotic lesions in RA. We also evaluated whether statins moderate the effects of inflammation (CRP) on CVD risk and on coronary plaque progression.Methods:One hundred-fifty patients underwent computed tomography angiography for coronary atherosclerosis evaluation (total, non-calcified, mixed/calcified plaque); 101 had repeat assessments within 6.9±0.3 years to evaluate plaque progression. CVD events were prospectively recorded, including cardiac death, myocardial infarction, unstable angina, revascularization, stroke, claudication, and heart failure hospitalization. Framingham-D’Agostino score assessed clinical risk. Plaque burden was measured as segment stenosis score (cumulative stenosis). Robust cox proportional hazards regression models evaluated the effects of time-varying statin use, log-transformed time-varying CRP (mg/dL) and their interaction on CVD risk controlling for Framingham-D’Agostino score, plaque burden and time-varying bDMARD use. Per-segment robust logistic regression assessed the effect of statin duration (years), log-transformed time-averaged CRP, and their interaction on likelihood of plaque formation in segments without plaque, and plaque regression or calcification in segments with non-calcified lesions. Models accounted for clustering of coronary segments within patients and controlled for Framingham-D’Agostino score, total prednisone dose, bDMARD duration, and time between scans.Results:Sixteen patients incurred 19 CVD events. There was no main effect of current statin use on CVD risk (adjusted HR 1.10, 95% CI 0.33-3.67). However, there was an interaction between current statin use and time-varying CRP (p-interaction=0.030); higher time-varying CRP predicted greater CVD risk in patients not receiving statins (adjusted HR 2.78, 95% CI 1.01-7.65), but not current statin users (Figure 1A). Likewise, current statin use associated with lower CVD risk when patients had higher time-varying CRP (&gt;0.5 mg/dL) but not when CRP was lower (&lt;0.5 mg/dL, Figure 1B). Statin duration had no main effect on new plaque formation in segments without plaque at baseline (adjusted OR 1.13, 95% CI 0.95-1.05); however, statin use moderated the effect of time-averaged CRP on new plaque formation (p-interaction=0.030, Figure 2A). Time-averaged CRP associated with a higher likelihood of new plaque in patients receiving statins less than one year (adjusted OR 1.75, 95% CI 1.38-2.20) but not those treated for longer (adjusted OR 1.26, 95% CI 0.78-2.02). In segments with non-calcified plaque, longer statin duration predicted protective calcification (adjusted OR 1.28, 95% CI 1.07-1.53, Figure 2B).Conclusion:In RA, statins moderated the effect of CRP on CVD event risk and new plaque formation in coronary segments without plaque. Longer statin duration was also associated with an increased likelihood of protective calcification of non-calcified plaque.Disclosure of Interests:George Karpouzas Grant/research support from: Pfizer, Consultant of: Sanofi-Genzyme-Regeneron, Janssen, Speakers bureau: Sanofi-Genzyme-Regeneron, BMS, Sarah Ormseth: None declared, Elizabeth Hernandez: None declared, Matthew Budoff: None declared

A biopolymer-based and inflammation-responsive nanodrug for rheumatoid arthritis treatment via inhibiting JAK-STAT and JNK signalling pathways.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease associated with progressive disability, systemic complications, and poor prognosis. The improved understanding of the roles of immune signaling pathway inhibitors has shed light on designing new and more effective approaches for RA treatment. In this work, an inflammation-responsive and molecularly targeted drug system has been developed for RA therapy. The drug carrier was synthesized by covalently grafting hydrophobic cholesterol (Chol) molecules onto a hydrophilic chondroitin sulfate (CS) chain via the inflammation-responsive diselenide bonds (SeSe). The resultant amphiphilic polymer CSSeSeChol readily forms nanoparticles (NPs) and encapsulates two kinase inhibitors tofacitinib and SP600125 in aqueous media. Upon administration into the RA mouse model, the nanodrug accumulates in RA lesions and releases the inhibitors for regulating the JAK-STAT and JNK pathways. As a result, the nanodrug exhibits satisfactory efficacy in RA treatment by suppressing the expression of relevant pro-inflammatory cytokines, blocking the activation of osteoclasts and providing protection for cartilage and joints.