Advanced Rheumatoid Arthritis Research Articles

Mesenchymal Stem Cell-Based Biomimetic Liposome for Targeted Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder that severely compromises joint health. The primary therapeutic strategy for advanced RA aims to inhibit joint inflammation. However, the nonspecific distribution of pharmacological agents has limited therapeutic efficacy and heightens the risks associated with RA treatment. To address this issue, we developed mesenchymal stem cell (MSC)-based biomimetic liposomes, termed MSCsome, which were composed of a fusion between MSC membranes and liposomes. MSC some with relatively simple preparation method effectively enhanced the targeting efficiency of drug to diseased joints. Interaction between lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 enhanced the affinity of the MSCsome for polarized macrophages, thereby improving its targeting capability to affected joints. The effective targeted delivery facilitated drug accumulation in joints, resulting in the significant inhibition of the inflammation, as well as protection and repair of the cartilage. In conclusion, this study introduced MSCsome as a promising approach for the effective treatment of advanced RA, providing a novel perspective on targeted drug delivery therapy for inflammatory diseases.

Coexistence of Bronchiectasis Related with Rheumatoid Arthritis and Posttuberculosis Lung Disease - An Everpresent Issue

Abstract The lung is a common site of involvement both in TB and rheumatoid arthritis (RA) disease, caused by disease itself or therapy. After completion of antiTB treatment, post TB lung disease (PTLD) residual changes persist and affect heath, survival and quality of life, mainly in patients with associated collagen diseases, as RA. Bronchiectasis are described in both RA and PTLD. The purpose of this prevalence study of bronchiectasis, performed among 92 RA hospitalized patients, from June 2017 to June 2019, consists in a pictorial assessment of the lung involvement changes, noticed on chest radiography and/or computed tomography, described in relation with TB sequelae, severity and duration of RA disease. Results. A high prevalence of imagistic abnormalities was found in 77.2% of cases (n=71/92). Bronchiectasis was a frequent imagistic chest finding (24/71; 33.8%), having a lower frequency among all study group patients (n=24/92; 26%), mostly older nonsmoker females. Conclusions. In a high TB burden, as Romania, the prevalence of bronchiectasis is related with advanced RA disease, being strongly correlated with persistent respiratory symptoms (p=0.009), and coexisting PTLD calcified nodular lung sequelae (p=0.001).

Targeting the vivid facets of apolipoproteins as a cardiovascular risk factor in rheumatoid arthritis.

Mostly, cardiovascular diseases are blamed for casualties in rheumatoid arthritis (RA) patients. Customarily, dyslipidemia is probably the most prevalent underlying cause of untimely demise in people suffering from RA as it hastens the expansion of atherosclerosis. The engagement of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), etc., is crucial in the progression and proliferation of both RA and abnormal lipid parameters. Thus, lipid abnormalities should be monitored frequently in patients with both primary and advanced RA stages. An advanced lipid profile examination, i.e., direct role of apolipoproteins associated with various lipid molecules is a more dependable approach for better understanding of the disease and selecting suitable therapeutic targets. Therefore, studying their apolipoproteins is more relevant than assessing RA patients' altered lipid profile levels. Among the various apolipoprotein classes, Apo A1 and Apo B are primarily being focused. In addition, it also addresses how calculating Apo B:Apo A1 ratio can aid in analyzing the disease's risk. The marketed therapies available to control lipid abnormalities are associated with many other risk factors. Hence, directly targeting Apo A1 and Apo B would provide a better and safer option.

Red emissive carbon dots Self-Cascading antioxidant nanozymes combine with anti-miRNA-155 for accurate monitoring and ameliorating rheumatoid arthritis

Accurate monitoring and effective antioxidant treatment strategies are highly desirable in rheumatoid arthritis (RA) amelioration. Herein, cerium (Ce) and selenium (Se) co-doped carbon dots (CS-CDs) integrated superoxide dismutase (SOD)-like and glutathione peroxidase (GPx)-like self-cascading catalytic activity are engineered. In this self-cascading nanozymes system, Ce active center catalyzes ·O2− to H2O2 by mimicking SOD, and the adjacent Se component sequentially decomposes the H2O2 by mimicking GPx, achieving enhanced catalytic and superior reactive oxygen species (ROS)-scavenging activities. CS-CDs further load cyanine-5 (Cy5)-labeled anti-miRNA-155 to realize macrophage subphenotype identification via miRNA-155 ratiometric imaging for RA accurate monitoring, and regulate the polarization of pro-inflammatory macrophages for synergistic RA amelioration. Comprehensive in vitro and in vivo experiments validate the advanced RA monitoring and therapy performance of the self-cascading nanozymes. This work not only offers a rationally designed self-cascading nanozyme with simple structures and intriguing ROS-scavenging capacity, but also opens up a strategy for accurate RA monitoring and synergistic amelioration.

Оценка эффективности тофацитиниба, упадацитиниба и олокизумаба у больных ревматоидным артритом в реальной клинической практике

Aim: to perform an indirect comparative analysis of changes over time in clinical and laboratory parameters of inflammatory activity of rheumatoid arthritis (RA) in patients who receive tofacitinib (TOFA), upadacitinib (UPA), and olokizumab (OKZ) in real clinical practice. Patients and Methods: the study included 30 patients with advanced RA and moderate or high activity (DAS28-ESR score) who had ineffective prior therapy with methotrexate, leflunomide, or genetically engineered biological drugs for at least 6 months. The patients were divided into three groups: 10 patients received TOFA 5 mg twice daily, 10 patients received UPA 15 mg daily, and 10 patients received OCZ 64 mg subcutaneously every 4 weeks. The patients underwent examination before treatment, as well as after 3 and 6 months. The serum level of interleukin 6 (IL-6) was measured using multiplex xMAP technology on the Bio-PlexTM 200 System analyzer (BIO-RAD, USA). Results: treatment with TOFA, UPA, and OCZ was associated with a decrease in DAS28-ESR, CDAI, SDAI, and HAQ-DI scores after 3 months. After 6 months, UPA was found to be superior to TOFA in terms of reducing CDAI and SDAI. Treatment with TOFA resulted in a decrease in IL-6 levels after 3 and 6 months. The study found that UPA did not have an effect on IL-6 levels. However, therapy with OCZ resulted in an increase in IL-6 levels after 3 months, followed by a decrease after 6 months. Despite this, IL-6 levels did not return to baseline values. Conclusion: the results of the study suggest that there are differences in the clinical effects of Janus kinase (JAK) inhibitors and OCZ in RA patients. Nevertheless, all drugs were found to be effective in suppressing RA activity, regardless of baseline IL-6 levels and changes during treatment. KEYWORDS: rheumatoid arthritis, interleukin 6, tofacitinib, upadacitinib, olokizumab, disease activity, therapy efficacy. FOR CITATION: Lapkina N.A., Baranov A.A., Leont'eva E.A., Amirdzhanova V.N., Kolin'ko A.A., Ashikhmin G.M. Efficacy of tofacitinib, upadacitinib and olokizumab in rheumatoid arthritis in real clinical practice. Russian Medical Inquiry. 2024;8(2):51–59 (in Russ.). DOI: 10.32364/2587-6821-2024-8-2-1.

Association of Serum IL-17 and IL-23 Cytokines With Disease Activity and Various Parameters of Rheumatoid Arthritis in Indian Patients.

Introduction Interleukin-23/T helper 17 (IL-23/Th17) axis cytokine has been thought to be a critical pathway for rheumatoid arthritis (RA) disease development and its association with disease severity, joint erosion, and functional outcome. There is a paucity of data on the role of IL-23/Th17 axis cytokines in an Indian RA subset of patients. We aimed to determinethe association between serum cytokines (interleukin-17 [IL-17] and [IL-23]) and disease activityas well as with clinical and biochemical parameters of RA patients. Methods In this observational cross-sectional study, 84 consecutive RA cases were recruited after obtaining consent. Serum IL-17 and IL-23 levels were measured by the enzyme-linked immunosorbent assay (ELISA) method. Clinical and laboratory parameters, disease activity score 28-erythocyte sedimentation rate (DAS28-ESR), and Health Assessment Questionnaire-II (HAQ-II) were recorded. Correlation of cytokines with various clinical and biochemical parameters was elicited. Results Only C-reactive protein (CRP) correlated positively with IL-23 (rs = 0.26, p = 0.014)but not the ESR. Both IL-17 and IL-23 levels showed an insignificant, weak positive correlation with the disease activity DAS28 (rs = 0.18, p = 0.097; rs = 0.12, p = 0.259, respectively). Neither IL-17 nor IL-23 levels differed among the disease severity group (p = 0.13, p = 0.215). Only the IL-23 level positively correlated with functional status (HAQ-II) (rs = 0.28, p = 0.009). IL-17 level was higher in advanced RA as compared to early RA (p = 0.028). Both IL-17 and IL-23 levels did not vary within the different subgroups (age, obesity, disease-modifying drugs/steroid/biologics use, and serology status). Conclusion Females had higher IL-23 levels than males. Advanced RA had higher IL-17 levels than early RA. The cytokinelevels were not influenced by factors like age, duration of disease, serology status, or drugs. Neither of the cytokines correlated significantly with disease severity. Higher IL-17 levels may have a role in the progression of early non-erosive to chronic erosive arthritis. Higher IL-23 levels may signal a bad functional outcome.

GLIOMA-05 A NOVEL CONCEPT FOR TREATMENT OF GLIOBLASTOMA: VAGUS NERVE ELECTRICAL STIMULATION FOR SUPPRESSION OF CYTOKINE (IL-6) SIGNALING

Abstract Glioblastoma is an aggressive, incurable cancer. Innovative approaches are urgently needed. There is resurgent interest in harnessing the power of the immune system (O’Rourke DM, 2017; Liau LM, 2023). Glioblastoma is a key target for cytokine reprogramming of the tumor microenvironment involving macrophages, monocytes, lymphocytes, and myeloid-derived cells. Furthermore, as with other cancers, the incidence and poor prognosis is linked to the age of the patient, and chronic, low-grade inflammation, or “inflammaging” (Franceschi, 2014). There is strong clinical, genomic (Coppola, 2014), preclinical data linking the progression of glioblastoma to the cytokine, IL-6. Yi Fan and colleagues (Wang, 2018; Yang, 2021) showed that blockade of IL-6 increases survival in mouse models of glioblastoma, an effect enhanced with the use of immune checkpoint blockade (ICB). These results were validated and extended by others (Tsukamoto, 2018; Lamano,2019). Taken together, we translated the findings to a prospective, multicenter clinical trial (NRG BRAIN-010, NCT04729959; PI, Stephen Bagley) for recurrent glioblastoma, combining stereotactic radiosurgery, IL-6R blockade (tocilizumab) and ICB (atezolizumab). To date, the regimen is well-tolerated with an acceptable safety profile. Vagus nerve stimulation is FDA-approved for control of medically refractory epilepsy. It is currently being evaluated in a multicenter, pivotal trial to treat advanced rheumatoid arthritis (RESET-RA, NCT04539964). Electrical stimulation of the vagus nerve activates the inflammatory reflex (Kelly, 2022), with a reduction of inflammatory cytokines, including IL-6 (Koopman, 2016). Electrical stimulation of the vagus nerve uses the ‘inflammatory reflex’ and exploits the cholinergic effect on T-cells (Levine, 2020). Taken together, we now propose a clinical trial to assess the safety and efficacy of vagal nerve stimulation for patients with glioblastoma and are in discussion with industry (SetPoint Medical) to design a prospective, clinical trial for treatment of glioblastoma.

Direct costs of rheumatoid arthritis multidisciplinary care in Ireland

Abstract Chronic diseases are at epidemic proportions and continuing to increase in both incidence and prevalence globally. Therefore, there is a growing need to assess and improve on the value currently provided within chronic care pathways. Examining a chronic disease, Rheumatoid Arthritis (RA), this study aimed to assess the cost associated with RA in primary and secondary care within the Health Service Executive in Ireland. Following mapping of the care pathway, patient vignettes based on exemplar RA patient types were used to conduct semi-structed interviews with every member of the primary (N = 21) and secondary care (N = 13) RA pathway. Overall cost of each patient type was calculated using time-driven activity-based costing along with medication and clinic running costs. Treating newly diagnosed RA patients costs second highest in primary (€337.39/year) and highest in secondary care (€922.32/year). While patients with advanced RA were most expensive to treat in primary (€469.18/year) and least costly in secondary care (€615.70/year). In primary care occupational therapists were the most expensive allied health care professionals (HCPs) at €1.19/min, followed by physiotherapists at €1.17/min. GP secretaries were the least costly at €0.30/min. In secondary care, consultant rheumatologists and phlebotomists were most and least costly respectively at €3.10 and €0.60/min/patient. Biological Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) cost significantly more (€8718.98/year) than Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) (€120.87/year). In terms of personnel cost newly diagnosed patients and patients with advanced RA are expensive to treat as these require more time with the HCPs. Being referred to departments outside of rheumatology such as orthopaedics, advanced RA patients cost less in secondary care. The difference between whether a patient was on a csDMARD or bDMARD had the biggest influence on total, overall costs amongst the RA patient. Key messages • The study provides a breakdown of costs of RA multidisciplinary care in Ireland, facilitating understanding cost drivers and potential areas for cost-savings. • The study advances the understanding of RA management in HSE Ireland.

The use of methotrexate in rheumatoid arthritis. Recommendations of the All-Russian public organization “Association of Rheumatologists of Russia”

Rheumatoid arthritis (RA) is the most frequent immunoinflammatory (autoimmune) rheumatic disease characterized by chronic erosive arthritis and systemic damage to internal organs. The data obtained in the course of basic research on deciphering the mechanisms of action of methotrexate (MT) and the materials of numerous randomized placebocontrolled trials, observational studies and national registries have strengthened the position of MT as the “gold standard” of RA pharmacotherapy and a key component of the “Treatment to Target” strategy. This was the basis for the development of new recommendations of the Association of Rheumatologists of Russia (ARR) concerning the use of MT in RA, according to which MT is considered as the drug of “choice” for induction and maintenance of remission in patients with early and advanced RA, including those who need combination therapy of MT with glucocorticoids, standard Disease-Modifying Antirheumatic Drugs (DMARDs), biologics and targeted synthetic DMARDs. Special attention is paid to the safety of MT therapy and the impact of MT on comorbid pathology associated with cardiovascular complications and interstitial lung disease. Implementation of the ARR recommendations into clinical practice will reduce the risk of disability and improve life prognosis in patients with RA.

Different Clinical Relevance of Anti-Citrullinated Protein Antibodies in RA Patients

The objective of the study was to find a potential relationship between ACPAs and disease activity, bone destruction, and ACPA responses to various therapeutic regimens. The study included 232 patients with rheumatoid arthritis (RA); 90 patients had early RA, and 142 patients had an advanced stage of the disease. 77 (85.6%) patients with early RA were highly positive for anti-CCP, and 29 (70.7%) patients were highly positive for anti-MCV. A positive correlation was found between anti-MCV and DAS28 (r = 0.4; p = 0.04). As for advanced RA, 78 (80.4%) patients were high-positive for anti-CCP, and 70 (79.5%) were high-positive for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r = 0.4; p = 0.02), as well as CDAI (r = 0.4; p = 0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0–122.0)) were found in pts highl-positive for anti-MCV (n = 79), compared to low-positive/negative (n = 27) patients (57.0 (31.0–88.0); p < 0.05). Anti-MCV levels dropped significantly in pts on rituximab and tocilizumab therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment. Anti-MCV levels correlated with inflammatory activity and development of bone destruction and decreased in pts on treatment. Anti-CCP was less responsive and showed minor changes during treatment; therefore, its thorough monitoring was not feasible.

Comparison of phenotypic properties of innate lymphoid cells at various stages of rheumatoid arthritis

Autoimmune diseases currently take a leading place in terms of frequency of occurrence in the population, among which 1 percent is occupied by rheumatoid arthritis (RA). Remission in this type of disease is extremely rare and requires constant use of pharmacotherapy. Studying the pathogenesis of RA is necessary to study to search for new drug targets. It is known that T helpers 1 (Th) and Th17 are involved in the development of RA. However, some researchers suggest that ILCs play a role in the development of RA. ILCs are “innate analogues” of Th, due to the fact that this subpopulation synthesizes the same cytokines. ILC1 is innate analogs of Th1, ILC2-Th2, ILC3-Th17. ILCs are tissue-resident innate lymphoid cells that have functional diversity and regulate the direction of the immune response through the production of cytokines.We used peripheral blood mononuclear cells (PBMCs) from patients (n = 19) and conditionally healthy donors (n = 10) as material. The group of patients was divided biologic disease-modifying anti-rheumatic drugs (bDMARDs) and Metotrexate (MTX) and of stage of RA (early and very early arthritis, advanced and late). PBMCs were stained with monoclonal antibodies. ILCs were identified as Lin-CD127+, CD294+ILCs (ILC2) were measured in the general population, CD117-CD294-ILCs were identified as ILC1, and CD117+CD294-ILCs were identified as ILC3.We obtained the following results: ILC1 was significantly reduced in patients treated with MTX comparison with patients on bDMARDs and healthy donors. However, patients on MTX with advanced RA had low levels of ILC2 and ILC3 compared to patients on bDMARDs. ILC2 significantly increased in patients with early stages of RA comparison with patients with advanced RA. However, ILC1 was significantly reduced in patients treated with MTX, and ILC3 increased significantly in patients treated with MTX comparison with bDMARDs. Expression of PD1 on ILC1 was increased compared to patients treated with bDMARDs. However, ILC3 patients with advanced stages on MTX had increased expression of PD1 comparison with patients taking bDMARDs. The ILC3 of donors was significantly increased comparison with patients on bDMARDs.

Circulating miRNA-19b as a biomarker of disease progression and treatment response to baricitinib in rheumatoid arthritis patients through miRNA profiling of monocytes.

A number of studies have demonstrated a key role of miRNA isolated from cells, tissue or body fluids as disease-specific biomarkers of autoimmune rheumatic diseases including rheumatoid arthritis (RA) and systemic sclerosis (SSc). Also, the expression level of miRNA is changing during disease development, therefore miRNA can be used as biomarkers monitoring RA progression and treatment response. In this study we have investigated the monocytes-specific miRNA that could serve as potential biomarkers of disease progression observed in sera and synovial fluids (SF) in early (eRA) and advanced (aRA) RA and in RA patients before and 3 months after selective JAK inhibitor (JAKi) -baricitinib treatment. Samples from healthy control (HC) (n=37), RA (n=44) and SSc (n=10) patients were used. MiRNA-seq of HC, RA, and SSc monocytes was performed to find versatile miRNA present in different rheumatic diseases. Selected miRNAs were validated in body fluids in eRA (<2 years disease onset) and aRA (>2 years disease onset) and RA patients receiving baricitinib. Using miRNA-seq, we selected top 6 miRNA out of 95 that were significantly changed in both RA and SSc monocytes compared to HC. To identify circulating miRNA predicting RA progression, these 6 miRNA were measured in eRA and aRA sera and SF. Interestingly, miRNA (-19b-3p, -374a-5p, -3614-5p) were significantly increased in eRA sera vs HC and even further upregulated in SF vs aRA sera. In contrast, miRNA-29c-5p was significantly reduced in eRA sera vs HC and even further decreased in SF vs aRA sera. Kegg pathway analysis predicted that miRNA were involved in inflammatory-mediated pathways. ROC analysis demonstrated that miRNA-19b-3p (AUC=0.85, p=0.04) can be used as biomarker predicting JAKi response. In conclusion, we identified and validated miRNA candidates which were present simultaneously in monocytes, sera, SF and that can be used as biomarkers predicting joint inflammation and monitoring therapy response to JAKi in RA patients.

Trends in characterization and analysis of TKA implants for 3D printing

In almost every country, knee joint problems are common among humans. As per American Academy of Orthopedic Surgeons, it is estimated that 3.5 million individuals in the world will undergo knee replacement surgery by 2030. People with advanced rheumatoid arthritis, or long-standing osteoarthritis are usually affected by this deformity due to changes in lifestyle. These conditions mainly affect middle-aged and elderly individuals with osteoarthritis or severe knee injuries. These problems can be overcome with the help of total knee implants by undergoing surgical procedures for providing relaxation &amp; comfort to the knee joint. These procedures are also known as total knee arthroplasty (TKA). TKA is an ancient surgical process employed for treating intracapsular knee joint arthritis. It is promising technique greatly augmenting a patient’s standard of life. The main components of TKA are femoral and tibial components, spacer, and patellar components respectively. Materials often used in these components include titanium, Ti6Al4V, cobalt-chromium alloys, polyethylene and bio compatible materials. 3D printing of TKA implants is a recent avenue being explored by researchers in an attempt to develop a better replacement for the conventional implants for providing comfort to the patients. This paper presents thorough assessment of research trends in mechanical characterization and finite element analysis of knee joint prosthetics, especially TKA implants for 3D printing.

Oral Microbiome in Pre-Rheumatoid Arthritis: The Role of Aggregatibacter Actinomycetemcomitans in Bacterial Composition.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that symmetrically affects the joints, eventually leading to cartilage and tissue destruction. While there are multiple etiologies for RA, from environmental to genetic risk factors, periodontal disease (PD) may contribute to the acceleration of RA symptoms in pre-rheumatoid arthritis (pre-RA) and RA patients. While PD is caused by multiple oral bacteria, this review explains the role of Aggregatibacter actinomycetemcomitans (Aa) in the pathogenesis of pre-RA and RA based on 13 primary articles. This paper focuses on the Aa virulence factor leukotoxin A (LtxA) because it has been reported to cause cellular destruction and inflammation in the oral cavity that can accelerate the development of RA. Individuals who are classified as pre-RA may benefit from periodontal screening to further reduce their risk of developing advanced RA. Additionally, they may benefit from earlier pharmacological therapy for RA using disease-modifying anti-rheumatic drugs (DMARD) and antibacterial treatment.

A Complete Atrioventricular Block Revealing Rheumatoid Arthritis: A Case Report

We report the case of a 66-year-old patient with cardiovascular risk factors: chronic smoking, diabetes and dyslipidemia. He went to the emergency room for syncope, with a complete atrioventricular block on the electrocardiogram. A transesophageal echocardiography performed as part of the workup shows a hyperechoic nodule located at the level of the interventricular. A transesophageal echocardiogram showed a hyperechoic nodule located at the level of the interventricular septum, which could correspond to a fibrous rheumatoid nodule and explain this atrioventricular block by the invasion of the conductive tissue. The patient was fitted with a definitive dual-chamber pacemaker. Conduction disorders in rheumatoid arthritis should be routinely detected in advanced rheumatoid arthritis. Transthoracic echocardiography is part of its workup. Transesophageal echocardiography may be necessary to detect fibrotic rheumatoid nodules.

Different clinical relevance of anti-citrullinated proteins antibodies in RA patients

Objective – to find a potential relationship between ACPA and disease activity, bone destruction, and ACPAs responses to various therapeutic regimens.Materials and methods. The study included 232 patients with rheumatoid arthritis (RA); 90 patients had early RA; 142 patients had advanced stage of the disease.Results. 77 (85.6%) patients with early RA were high positive for anti-CCP, and 29 (70.7%) patients – high positive for anti-MCV. A positive correlation was found between anti-MCV and DAS28 (r=0.4; p=0.04). As for advanced RA, 78 (80.4%) patients were high positive for anti-CCP, and 70 (79.5%) – for anti-MCV. There was a positive correlation between anti-MCV concentration and SDAI (r=0.4; p=0.02), as well as CDAI (r=0.4; p=0.02). No significant correlations were found between the anti-CCP levels and activity indices, anti-CCP and acute-phase parameters in both early and advanced RA groups. Higher total Sharp scores (96.5 (65.0–122.0)) were found in pts high positive for anti-MCV (n=79), compared to low-positive/negative (n=27) patients (57.0 (31.0–88.0); p&lt;0.05). Anti-MCV levels dropped significantly in pts on rituximab and tocilizumab therapy at weeks 12 and 24 after initiation of treatment, while high anti-CCP concentration persisted throughout the treatment.Conclusion. Anti-MCV levels correlated with inflammatory activity and development of bone destruction, and were decreasing in pts on treatment. Anti-CCP was less responsive, showed minor changes during treatment, therefore its’ thorough monitoring was not feasible.

Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes.

Objective:Rheumatoid arthritis is a chronic inflammatory autoimmune disease that can lead to synovial damage, persistent joint pain, and functional disability. Our objective was to evaluate baseline synovial transcriptome from early inflammatory arthritis patients (EIA) and identify pretreatment biomarkers that could potentially provide insights into long-term functional outcomes of rheumatoid arthritis (RA).MethodsSynovial biopsies from clinically inflamed knee joints were procured from either 17 EIA patients before initiation of disease modifying anti-rheumatic drug (DMARD) therapy (DMARD-naïve EIA) using the minimally invasive closed needle biopsy technique or advanced RA patients undergoing arthroplasty. Affymetrix Human Genome U133 Plus 2 microarray platform was used to profile the synovial transcriptome. The cohort was followed clinically for a median of 12.3 years, and patient data was collected at each visit. Short-term and long-term clinical outcomes were determined by assessing RA-associated clinical parameters Statistical adjustments were made to account for asynchronous clinical visits and duration of follow up.ResultsBased on the transcriptomic analysis, we identified 5 differentially expressed genes (DEGs), including matrix metalloproteinase (MMP)-1 (fibroblast collagenase) and MMP-3 (stromelysin-1) in DMARD-naïve EIA patients, relative to advanced RA patients (q < 0.05). Dichotomous expression of MMP-1 and MMP-3 mRNA and protein was confirmed by qPCR and immunohistochemistry respectively, based on which DMARD-naïve EIA subjects were classified as MMP-high or MMP-low. Hierarchical clustering of transcriptomic data identified 947 DEGs between MMP-high and MMP-low cohorts. Co-expression and IPA analysis of DEGs in the MMP-high cohort showed an enrichment of genes that participated in metabolic or biochemical functions and intracellular immune signaling were regulated through NF-κB and β-catenin complexes and correlated with markers of systemic inflammation. Analysis of short-term clinical outcomes in MMP-high cohort showed a significant reduction in the DAS-CRP scores relative to baseline (P <0.001), whereas area under the curve analyses of modified HAQ (mHAQ) scores correlated negatively with baseline MMP-1 (R = −0.59, P = 0.03). Further, longitudinal mHAQ scores, number of swollen joints, number of DMARDs and median follow-up duration appeared to be higher in MMP-low cohort.ConclusionOverall, our results indicate that the gene expression profiling of synovial biopsies obtained at the DMARD-naive stage in patients with EIA categorizes them into subsets with varying degrees of inflammation and can predict the future of long-term clinical outcome.

Nanoenzyme engineered neutrophil-derived exosomes attenuate joint injury in advanced rheumatoid arthritis via regulating inflammatory environment.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and destruction of cartilage, promoted by sustained inflammation. However, current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint. Inspired by neutrophil chemotaxis for inflammatory region, we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles (uPB-Exo) via click chemistry, inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties. uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes, subsequently neutralizing pro-inflammatory factors, scavenging reactive oxygen species, and alleviating inflammatory stress. In addition, uPB-Exo effectively targeted to inflammatory synovitis, penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system, leading to precise diagnosis of RA in vivo with high sensitivity and specificity. Particularly, uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation, thereby significantly ameliorating joint damage. Therefore, nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.

Amidst the chaos of late rheumatoid arthritis with no treatment

A 78-year-old man with 24 years history of Rheumatoid Arthritis (RA) came with neck pain. He always refused any treatment except for NSAIDs. From 2 years ago, he was bedridden. He was chronic cigarette smoker. On examination, he had rheumatoid nodules, severe both hands deformity, elbows flexion contracture and knee joints limitation of motion. His lab tests showed high titer of rheumatoid factor and anti cyclic citrullinated protein antibody, high ESR, CRP and vitamin D deficiency. Radiologic studies showed multiple vertebral osteoporotic fractures. Cervical spine CT scan (a and b) showed destruction of the odontoid process and fusion of facet joints of the C2, C3 and C4. MRI of cervical spine (c) showed destruction of odontoid process surrounding by inflammatory synovitis. CT scan of lung (e and f) showed multiple upper lobeand sub pleural nodules along fibrotic changes in base of right lobe. X-ray of knee and hip (d and g) showed severe osteoarthritis andsite of previouship nailing. The patient was diagnosed with advanced erosive nodular RA, severe secondary osteoporosis, osteoarthritis and rheumatoid lung. Standard treatment was recommended, although he again refused. RA can result in progressive joint destruction, deformity and disability [1]. In the spine, it has a predilection for the cervical area, leads to odontoid erosion, spinal instability, and subluxation. In the era of importance of early treatment, these complications are rarely seen, however despite biologic therapy, it has been shown that 15-30% of RA patients can still have preclinical cervical spine abnormalities [2]. The Osteoporosis (OP) is more frequent in patients with high disease activity, bone erosions, &gt;10 years disease duration, and high titers of anti-CCP and RF positivity [3]. Our patient with multiple poor prognostic factors for erosive RA came with extra articular and complications of this disease due refusing treatment.

CONSTRAINED HINGED ELBOW ARTHROPLASTY IN AN BONY ANKYLOSED ELBOW WITH NON UNION SUPRACONDYLAR FRACTURE HUMERUS: A CASE REPORT

Ankylosis of elbow is a very difcult case to treat. Now Total elbow arthroplasty (TEA) in managing ankylosis at elbow has evolved much in the recent times and is also most common surgical procedure used in the management of advanced bony ankylosis , rheumatoid arthritis, posttraumatic arthritis, osteoarthritis, and difcult fracture around elbow joint in elderly patients. Ÿ TEA for ankylotic elbows in elderly patients with nonunion supracondylar fracture is a good surgical option to restore adequate function of elbow joint. Total elbow prostheses have progressed over the time and now include the constrained, semiconstrained, and modular Ÿ Other joints in the extremity should be carefully examined, as well as the elbow's mobility and function, in order to construct a complete preand post-operative management plan that considers the upper extremity's whole range of motion.. Ÿ However, long-term complications, including infection, aseptic loosening, instability, and periprosthetic fracture, remain a challenge. Complication rates, reoperation rates, and survivorship of modern prostheses are discussed. Technical pearls and pitfalls are discussed