Rheumatoid Arthritis Joint Research Articles

Modulation of Dopamine Receptors on Osteoblasts as a Possible Therapeutic Strategy for Inducing Bone Formation in Arthritis.

Rheumatoid arthritis (RA) is associated with systemic osteoporosis, which leads to severe disability and low quality of life. Current therapies target osteoclasts to reduce bone degradation, but more treatment options would be required to promote bone protection by acting directly on osteoblasts (OB). Recently, the local production of dopamine in inflamed joints of RA has been observed. Thus, in this project, we aimed to determine the implication of the neurotransmitter dopamine in the bone formation process in RA. Dopamine receptors (DR) in the human bone tissue of RA or osteoarthritis (OA) patients were examined by immunohistochemistry. DR in isolated human osteoblasts (OB) was analyzed by flow cytometry, and dopamine content was evaluated by ELISA. Osteoclasts (OC) were differentiated from the PBMCs of healthy controls (HC) and RA patients. Isolated cells were treated with specific dopamine agonists. The effect of dopamine on mineralization was evaluated by Alizarin red staining. Cytokine release in supernatants was measured by ELISA. Osteoclastogenesis was evaluated with TRAP staining. OC markers were analyzed via real-time PCR and bone resorption via staining of resorption pits with toluidine blue. All DR were observed in bone tissue, especially in the bone remodeling area. Isolated OB maintained DR expression, which allowed their study in vitro. Isolated OB expressed tyrosine hydroxylase, the rate-limiting enzyme for dopamine production, and contained dopamine. The activation of D2-like DR significantly increased bone mineralization in RA osteoblasts and increased osteoclastogenesis but did not alter the expression of OC markers nor bone resorption. DR were found in the bone remodeling area of human bone tissue and dopamine can be produced by osteoblasts themselves, thus suggesting a local autocrine/paracrine pathway of dopamine in the bone. D2-like DRs are responsible for bone mineralization in osteoblasts from RA patients without an increase in bone resorption, thus suggesting the D2-like DR pathway as a possible future therapeutic target to counteract bone resorption in arthritis.

Systematic analysis of inflammation and pain pathways in a mouse model of gout.

Gout is a prevalent and painful inflammatory arthritis, and its global burden continues to rise. Intense pain induced by gout attacks is a major complication of gout. However, systematic studies of gout inflammation and pain are lacking. Using a monosodium urate (MSU) crystal-induced gout model, we performed genome-wide transcriptome analysis of the inflamed ankle joint, dorsal root ganglion (DRG), and spinal cord of gouty mice. Our results revealed important transcriptional changes, including highly elevated inflammation and broad activation of immune pathways in both the joint and the nervous system, in gouty mice. Integrated analysis showed that there was a remarkable overlap between our RNAseq and human genome-wide association study (GWAS) of gout; for example, the risk gene, stanniocalcin-1 (STC1) showed significant upregulation in all three tissues. Interestingly, when compared to the transcriptomes of human osteoarthritis (OA) and rheumatoid arthritis (RA) joint tissues, we identified significant upregulation of cAMP/cyclic nucleotide-mediated signaling shared between gouty mice and human OA with high knee pain, which may provide excellent drug targets to relieve gout pain. Furthermore, we investigated the common and distinct transcriptomic features of gouty, inflammatory pain, and neuropathic pain mouse models in their DRG and spinal cord tissues. Moreover, we discovered distinct sets of genes with significant differential alternative splicing or differential transcript usage in each tissue, which were largely not detected by conventional differential gene expression analysis approaches. Based on these results, our study provided a more accurate and comprehensive depiction of transcriptomic alterations related to gout inflammation and pain.

Emerging proteoglycans and proteoglycan-targeted therapies in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease that causes inflammation of the joints and damage to the cartilage and bone. The pathogenesis of RA is characterized in many patients by the presence of antibodies against citrullinated proteins. Proteoglycans are key structural elements of extracellular matrix in the joint articular cartilage and synovium and are secreted as lubricants in the synovial fluid. Alterations of proteoglycans contribute to RA pathogenesis. Proteoglycans such as aggrecan can be citrullinated and become potential targets of the rheumatoid autoimmune response. Proteoglycans are also upregulated in RA joints and/or undergo alterations of their regulatory functions over cytokines and chemokines, which promotes inflammation and bone damage. Recent studies have aimed to not only clarify these mechanisms but also develop novel proteoglycan-modulating therapeutics. These include agents altering the function and signaling of proteoglycans as well as tolerizing agents targeting citrullinated aggrecan. This mini-review summarizes the most recent findings regarding the dysregulation of proteoglycans that contributes to RA pathogenesis and the potential for proteoglycan-modulating agents to improve upon current RA therapy.

Targeting protein–protein interaction for immunomodulation: A sunflower trypsin inhibitor analog peptidomimetic suppresses RA progression in CIA model

Protein–protein interactions (PPI) of co-stimulatory molecules CD2-CD58 are important in the early stage of an immune response, and increased expression of these co-stimulatory molecules is observed in the synovial region of joints in rheumatoid arthritis (RA) patients. A CD2 epitope region that binds to CD58 was grafted on to sunflower trypsin inhibitor (SFTI) template structure to inhibit CD2-CD58 PPI. The peptide was incorporated with an organic moiety dibenzofuran (DBF) in its structure. The designed peptidomimetic was studied for its ability to inhibit CD2-CD58 interactions in vitro, and its thermal and enzymatic stability was evaluated. Stability studies indicated that the grafted peptidomimetic was stable against trypsin cleavage. In vivo studies using the collagen-induced arthritis (CIA) model in mice indicated that the peptidomimetic was able to slow down the progress of arthritis, an autoimmune disease in the mice model. These studies suggest that with the grafting of organic functional groups in the stable peptide template SFTI stabilizes the peptide structure, and these peptides can be used as a template to design stable peptides for therapeutic purposes.

P078 International impact of a co-produced training video: self-examination of tender and swollen joints for people with rheumatoid arthritis

Background/AimsPatients with rheumatoid arthritis (RA) need support to understand and manage their condition. The COVID-19 pandemic rapidly transformed outpatient clinical consultations from face-to-face towards remote models. This increased the emphasis placed upon self-assessment of joints and disease activity, strengthening the need for patient education materials. We planned to develop a video to support patient research participants to monitor disease activity remotely using the REMORA app. We altered the video’s scope and made it open access to meet the need created by changes in service delivery models.MethodsA video demonstrating self-examination of tender and swollen joints in RA was co-produced with patients and the multi-disciplinary team. A nurse consultant introduces key concepts, (how to identify and examine tender and swollen joints, which joints to include, etc), coaches a patient through self-examination, and answers key questions. Materials co-produced to support implementation into practice include a joint count manikin and table, an advertising poster, and blogs. Collaboration with international research colleagues has led to the production of a version dubbed in German. Subtitles are available in German and Hindi. Online feedback was sought via a survey. Ethical approval was not required as all contributors acted as equal members of the research team.ResultsThe 15-minute video, supporting materials and survey were uploaded to YouTube in February 2021 [tinyurl.com/REMORAvideo]. 1,000 hits were received in week one, reaching >12,500 after eight months. 20% of viewers are UK-based, 15% from the USA, 10% from India. 26% of views used English subtitles, 0.2% German, 0.1% Hindi. 124/125 people engaging with the ‘like/dislike’ function on YouTube, ‘liked’ the video. 48 people fed-back online (26 patients, 22 clinicians). Patient ages were: 18-35(5%), 36-55(62%), 56-75(29%), 76 + (5%), the majority of whom were female (19/21[91%]). Before watching, 14/17(82%) patients rated themselves as ‘poor’-‘fair’ at self-examination: after watching, the same number rated themselves as ‘good’-‘excellent’. 19/21(90%) and 17/21(81%) patients respectively either somewhat or strongly agreed with the statements ‘I now feel confident to self-examine for’ ‘tender’ or ‘swollen’ joints. 19/21(90%) of patients and 13/17(77%) clinicians either somewhat or strongly agreed with the statement that ‘the video fulfilled my expectations’. 18/21(86%) patients and 12/17(71%) clinicians would recommend the video. To date, several national organisations have engaged with the video. It supports the BSR ePROMS platform and national audit. The National Rheumatoid Arthritis Society plans to incorporate it into the ‘Know your DAS app’, and it will contribute to an NHSX playbook of digital best practice.ConclusionThis co-produced training video for people with RA, originally intended to support a remote monitoring app, has been well-received, with much wider-reaching international impact than anticipated. This demonstrates the need for materials collaboratively designed with patients to support patient self-management of long-term conditions, in the digital era.Disclosure C.A. Sharp: None. K. Staniland: None. T. Cornell: Corporate appointments; T.C. is an employee of Abbvie, working as a Rheumatology Nurse Consultant. Shareholder/stock ownership; T. C. is a shareholder of shares in Abbvie. W.G. Dixon: Consultancies; WGD has received consultancy fees from Abbvie and Google, unrelated to this work.

Peripheral distributions of IL-4-producing CD4 + T cells and CD4 + CD25 + FoxP3 + T cells (Tregs) in rheumatoid arthritis patients with poor response to therapy are associated with HLA shared epitope alleles and ACPA status.

Specific profiling of CD4 + T cell subsets in the circulation and inflamed joints of rheumatoid arthritis (RA) patients may have therapeutic implications. This study aimed to evaluate the peripheral distributions of Th2 and Treg cells in relation to HLA-shared epitope (SE) alleles and anti-cyclic citrullinated peptide antibody (ACPAs) status in patients with good response (GR) and poor response (PR) to treatment. The frequencies of IL-4-producing CD4 + T cells (Th2) and CD4 + CD25 + Foxp3 + T cells (Tregs) were determined by flow cytometry in 167 RA patients including 114 GR and 53 PR cases. CD4 + T cell subsets were also analyzed based on HLA-SE and ACPAs statuses. One hundred nine of 167 patients were positives for HLA-SE, 63.4% for ACPAs, 43.7% for SE/ACPAs and 14.9% were negatives for SE/ACPAs. Higher frequencies of Th2 (P = 0.001) and Treg cells (P = 0.03) were found in the patients versus controls. Increased and decreased frequencies of Th2 and Tregs cells were observed in the PR versus GR patients respectively (P = 0.003 and P = 0.004). Higher proportions of Th2 cells were observed in the SE+RA versus SE-RA (P = 0.001), in ACPA+RA versus ACPA-RA (P = 0.005) and in the SE+ACPA+RA versus SE-ACPA-RA patients (P = 0.002). Treg cells frequencies decreased in the SE+RA versus SE-RA (P = 0.03) and in SE+ACPA+RA versus SE-ACPA-RA (P = 0.02). ACPA+GR and SE+PR patients showed higher proportions of Th2 cells than ACPA-GR and SE-PR patients respectively (P = 0.02 and P = 0.01). Analysis of the CD4 + T cell subsets profiles in conjunction with genetic background and autoantibodies patterns can be useful for precise therapeutic response monitoring in the RA patients.

Pain and wrist joint in rheumatoid arthritis: The impact on functional capacity

Enquadramento: Artrite reumatoide (AR), doença autoimune, inflamatória e crónica. Caracteriza-se por poliartrite, dor crónica e dificuldade em mobilizar as articulações, que levam à incapacidade funcional dos doentes. Objetivos: Avaliar a influência da mobilidade articular do punho e da dor, na capacidade funcional de doentes com AR. Metodologia: Estudo quantitativo, descritivo e correlacional, constituído por uma amostra de 105 doentes, com aplicação do Índice de Incapacidade - Questionário Avaliação de Saúde (HAQ-DI); Escala Visual Analógica da Dor (EVA) e medição da amplitude articular do punho, com goniómetro. Resultados: A mobilidade articular do punho é representativa na funcionalidade (p < 0,05), no entanto, a sua extensão e flexão, não influenciam diretamente a dor (p > 0,05). Observou-se que a dor é impactante na capacidade funcional dos doentes (p = 0,010). Conclusão: A mobilidade articular do punho e a dor afetam as atividades diárias dos doentes com AR, expressas através da capacidade funcional de avaliação de saúde.

Rheumatoid Arthritis: Early diagnosis and treatment outcomes with individualized Homoeopathic medicine: A single blind, simple randomized placebo controlled study

Introduction: Rheumatoid Arthritis (RA) is the most common inflammatory articular disorder. It is a chronic progressive systemic autoimmune disease with hallmark of chronic erosive-polyarthritis. It can be seen in all races with overall prevalence of about 1 percent. Its prevalence in old women is about 5 percent and female to male ratio is 3 to 1 in this disorder with the peak onset age of 50 ± 15 years .The clinical feature of RA is divided to three categories such as Articular, Peri-articular, Extra-articular (systemic). Research Objectives: To study the response of Homoeopathic medicaments in RA with response to change in Disease Activity Scores in 28 joints (DAS28).Methodology: The study was simple randomized and single blind method. The sample size was fixed at 90.Test group 60 i.e. Group - I(Centesimal -30), Group – II( 50 Millesimal -30 ) & Group – III( Control) 30. Duration of study was for two years. It was carried out at International Study & Research Centre on Homoeopathy, Bhubaneswar. There were inclusion & exclusion criteria, treatment plan, follow up with disease activity scores in 28 joints (DAS28) of RA. Results: Were documented before and after with change in RA severity, which was assessed by Disease Activity Scores in 28 joints (DAS28). Before treatment the data were collected as per DAS28 and categorized into low disease activity, moderate disease activity and high disease activity. After intervention as per the “DAS28 improvement over time points” the response was recorded. As per the guidelines above data were interpreted in results.Statistical Analysis: Chi-square test for comparision of centesimal potency and placebo the chi-square equals to 32.593 with 1 degree of freedom. The two tailed P value is less than 0.0001. Hence the result was statistically significant difference (P

PENGALAMAN PENGASUH DALAM MERAWAT LANSIA DENGAN PENYAKIT KRONIS REMATIK DI WILAYAH JANGKAUAN LKS LU MANDAR INDONESIA DESA BUKU

The aging process is a life cycle characterized by the decline in various organ functions in the body which is marked by the susceptibility of the body to various disease attacks. As for the changes, it affects the deterioration of physical health which in turn will affect the susceptibility to disease. Rheumatic disease and joint inflammation are diseases that are often found in the community, especially in people aged 40 years and over. More than 40 percent of these age groups suffer from complaints of joint and muscle pain. This study aims to determine the experience of caregivers in caring for the elderly with chronic rheumatic disease in Buku Village, Mapilli District, Polewali Mandar Regency, West Sulawesi Province. . The method used in this research is to use qualitative research where this research is a method to find answers to elderly cargiver. The sample was 5 elderly respondents who were made as respondents. Results of the study] The experience of caregivers in caring for the elderly with chronic rheumatic disease, there were 5 respondents who were carried out by the research. From the results of the conversation above, it can be concluded that the Caregiver plays an important role in treating the Elderly with Chronic Rheumatic Disease.

Extramucosal Formation and Prognostic Value of Secretory Antibodies in Rheumatoid Arthritis.

To investigate levels and possible extramucosal formation of secretory Ig, including anti-citrullinated protein antibodies (ACPAs), in rheumatoid arthritis (RA). Three patient groups were studied: 1) ACPA-positive patients with musculoskeletal pain without clinical arthritis, 2) patients with recent-onset RA, and 3) patients with established RA. In baseline serum samples (groups 1 and 2) and paired synovial fluid samples (group 3), we analyzed total secretory IgA, total secretory IgM, free secretory component (SC), and SC-containing ACPA. Extramucosal formation of SC-containing ACPA was investigated by preincubating RA sera and affinity-purified ACPA with recombinant free SC. Compared to healthy controls, serum levels of total secretory IgA and total secretory IgM were increased both in patients with early RA and at-risk patients (P < 0.05). Patients with early RA with elevated total secretory Ig had significantly higher disease activity during the 3-year follow-up period compared to those without increased levels. At-risk patients who developed arthritis during follow-up (39 of 82) had higher baseline total secretory IgA levels compared to those who did not (P = 0.041). In established RA, total secretory IgA and total secretory IgM levels were higher in serum than in synovial fluid (P < 0.0001), but SC-containing ACPAs adjusted for total secretory Ig concentration were higher in synovial fluid (P < 0.0001). Preincubation with recombinant free SC yielded increased SC-containing ACPA reactivity in sera as well as in affinity-purified IgA and IgM ACPA preparations. Circulating secretory Ig are elevated before and at RA onset. In the presence of free SC, secretory Ig may form outside the mucosa, and SC-containing ACPAs are enriched in RA joints. These findings shed important new light on the mucosal connection in RA development.

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.

Controversial Aspects of Diagnostics and Therapy of Arthritis of the Temporomandibular Joint in Rheumatoid and Juvenile Idiopathic Arthritis-An Analysis of Evidence- and Consensus-Based Recommendations Based on an Interdisciplinary Guideline Project.

Introduction: Due to potentially severe sequelae (impaired growth, condylar resorption, and ankylosis) early diagnosis of chronic rheumatic arthritis of the temporomandibular joint (TMJ) and timely onset of therapy are essential. Aim: Owing to very limited evidence the aim of the study was to identify and discuss controversial topics in the guideline development to promote further focused research. Methods: Through a systematic literature search, 394 out of 3771 publications were included in a German interdisciplinary guideline draft. Two workgroups (1: oral and maxillofacial surgery, 2: interdisciplinary) voted on 77 recommendations/statements, in 2 independent anonymized and blinded consensus phases (Delphi process). Results: The voting results were relatively homogenous, except for a greater proportion of abstentions amongst the interdisciplinary group (p < 0.001). Eighty-four percent of recommendations/statements were approved in the first round, 89% with strong consensus. Fourteen recommendations/statements (18.2%) required a prolonged consensus phase and further discussion. Discussion: Contrast-enhanced MRI was confirmed as the method of choice for the diagnosis of TMJ arthritis. Intraarticular corticosteroid injection is to be limited to therapy-refractory cases and single injection only. In adults, alloplastic joint replacement is preferable to autologous replacement. In children/adolescents, autologous reconstruction may be performed lacking viable alternatives. Alloplastic options are currently still considered experimental.

Ebosin Attenuates the Inflammatory Responses Induced by TNF-α through Inhibiting NF-κB and MAPK Pathways in Rat Fibroblast-Like Synoviocytes.

Tumor necrosis factor-α (TNF-α) lies at the apex of signal transduction cascades that results in induced destruction of joints in rheumatoid arthritis. It is therefore of great medicinal interest to modulate the cellular responses to TNF-α. Ebosin, a novel exopolysaccharide derived from Streptomyces sp, has been demonstrated to have remarkable therapeutic actions on collagen-induced arthritis in rats, while it also suppressed the production of IL-1β, TNF-α, and IL-6 at both mRNA and protein levels in cultured fibroblast-like synoviocytes. In order to further understand the potential mechanisms involved in the anti-inflammatory effects of ebosin at molecular level, we investigated the impact of it on the activation of MAPK and NF-κB pathways following TNF-α induced in fibroblast-like synoviocytes (FLS). The results showed that the phosphorylation levels of TNF-α-induced p38, JNK1, JNK2, IKKα, IKKβ, and IκB, as well as NF-κB nuclear translocation, were reduced significantly in FLS cells in response to ebosin. Furthermore, we proved that ebosin decreased the level of NF-κB in the nucleus and blocked the DNA-binding ability of NF-κB using electrophoresis mobility gel shift assay. Besides, low levels of matrix metalloproteinases (MMP-1 and MMP-3) and chemokines (interleukin-8 and RANTES) were found in TNF-α-stimulated fibroblast-like synoviocytes treated with ebosin. These results indicate that ebosin can suppress a range of activities in both MAPK and NF-κB pathways induced by TNF-α in rat fibroblast-like synoviocytes, which provides a rationale for examining the use of ebosin as a potential therapeutic candidate for rheumatic arthritis.

Deep Learning-Based Classification of Inflammatory Arthritis by Identification of Joint Shape Patterns-How Neural Networks Can Tell Us Where to "Deep Dive" Clinically.

Objective:We investigated whether a neural network based on the shape of joints can differentiate between rheumatoid arthritis (RA), psoriatic arthritis (PsA), and healthy controls (HC), which class patients with undifferentiated arthritis (UA) are assigned to, and whether this neural network is able to identify disease-specific regions in joints.MethodsWe trained a novel neural network on 3D articular bone shapes of hand joints of RA and PsA patients as well as HC. Bone shapes were created from high-resolution peripheral-computed-tomography (HR-pQCT) data of the second metacarpal bone head. Heat maps of critical spots were generated using GradCAM. After training, we fed shape patterns of UA into the neural network to classify them into RA, PsA, or HC.ResultsHand bone shapes from 932 HR-pQCT scans of 617 patients were available. The network could differentiate the classes with an area-under-receiver-operator-curve of 82% for HC, 75% for RA, and 68% for PsA. Heat maps identified anatomical regions such as bare area or ligament attachments prone to erosions and bony spurs. When feeding UA data into the neural network, 86% were classified as “RA,” 11% as “PsA,” and 3% as “HC” based on the joint shape.ConclusionWe investigated neural networks to differentiate the shape of joints of RA, PsA, and HC and extracted disease-specific characteristics as heat maps on 3D joint shapes that can be utilized in clinical routine examination using ultrasound. Finally, unspecific diseases such as UA could be grouped using the trained network based on joint shape.

Diagnosis of Metacarpophalangeal Synovitis with Musculoskeletal Ultrasound Images.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can result in considerable disability and pain. The metacarpophalangeal (MCP) joint is the most common diseased joint in RA. In clinical practice, MCP synovitis is commonly diagnosed on the basis of musculoskeletal ultrasound (MSUS) images. However, because of the vague criteria, the consistency in grading MCP synovitis based on MSUS images fluctuates between ultrasound imaging practitioners. Therefore, a new method for diagnosis of MCP synovitis is needed. Deep learning has developed rapidly in the medical area, which often requires a large-scale data set. However, the total number of MCP-MSUS images fell far short of the demand, and the distribution of different medical grades of images was unbalanced. With use of the traditional image augmentation methods, the diversity of the data remains insufficient. In this study, a high-resolution generative adversarial network (HRGAN) method that generates enough images for network training and enriches the diversity of the training data set is described. In comparison experiments, our proposed diagnostic system based on MSUS images provided more consistent results than those provided by clinical physicians. As the proposed method is image relevant, this study might provide a reference for other medical image classification research with insufficient data sets.

Clinical results of a 10-year follow-up of surgical treatment for elbow stiffness in rheumatoid arthritis: A case series

BackgroundRheumatoid arthritis commonly causes transient limitation of joint motion, but the treatment of persistent stiffness in the rheumatoid elbow has rarely been reported. The purpose of this study was to evaluate the long-term clinical results of surgical treatment of rheumatoid elbow stiffness. MethodsSurgical treatment, including open arthrolysis with hinged external fixation, total synovectomy, and ulnar nerve release and anteriorization, was performed in 48 elbows in 43 patients with rheumatoid arthritis and early joint destruction. Mobility (flexion-extension and pronation-supination), Mayo Elbow Performance Score (MEPS), visual analog scale (VAS) score, muscle strength, nerve symptoms, postoperative complications, and recurrent synovitis were evaluated 9–11 years (average, 9.88 years) postoperatively. ResultsThe mobility of the elbow was significantly improved over the preoperative period either in extension, flexion, protonation, supination (P < .001, P < .001, P < .001, P = .002). The mean MEPS was significantly improved from 56.25 points (range, 30–90) to 87.40 points (range, 40–100) (P < .001). The pain was relieved, and the mean VAS score was reduced from 3.56 (range, 0–8) to 1.08 (range, 0–5) points (P < .001). Preoperative ulnar nerve symptoms were observed in 17 patients and relieved in 10 (59%) patients, and the mean Amadio score was raised from 6.9 (range, 3–9) to 7.96 (range, 4–9) points (P < .001). Through surgical treatment and postoperative rehabilitation, the mean grip strength of the patients was significantly improved from an average of 9.01 (range, 3.4–18.5) to 17.56 kg (range, 3.9–40.2) (P < .001). Five elbows developed recurrent synovitis, and one underwent total elbow arthroplasty. Postoperative complications were uncommon and not severe. ConclusionSurgical treatment is a reliable procedure for rheumatoid elbow stiffness and can be effective in improving elbow mobility, function, muscle strength, pain relief, and relief of nerve symptoms.

Macrophage-Targeted Hydroxychloroquine Nanotherapeutics for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is an autoimmune disease with unclear pathogenesis. Hydroxychloroquine (HCQ), despite its moderate anti-RA efficacy, is among the few clinical drugs used for RA therapy. Macrophages reportedly play a vital role in RA. Here, we designed and explored macrophage-targeted HCQ nanotherapeutics based on mannose-functionalized polymersomes (MP-HCQ) for RA therapy. Notably, MP-HCQ exhibited favorable properties of less than 50 nm size, glutathione-accelerated HCQ release, and M1 phenotype macrophage (M1M) targetability, leading to repolarization of macrophages to anti-inflammatory M2 phenotype (M2M), reduced secretion of pro-inflammatory cytokines (IL-6), and upregulation of anti-inflammatory cytokines (IL-10). The therapeutic studies in the zymosan-induced RA (ZIA) mouse model showed marked accumulation of MP-HCQ in the inflammation sites, ameliorated symptoms of RA joints, significantly reduced IL-6, TNF-α, and IL-1β, and increased IL-10 and TGF-β compared with free HCQ. The analyses of RA joints disclosed greatly amplified M2M and declined mature DCs, CD4+ T cells, and CD8+ T cells. In accordance, MP-HCQ significantly reduced the damage of RA joints, cartilages, and bones compared to free HCQ and non-targeted controls. Macrophage-targeted HCQ nanotherapeutics therefore appears as a highly potent treatment for RA.

Three-dimensional spatial transcriptomics uncovers cell type localizations in the human rheumatoid arthritis synovium

The inflamed rheumatic joint is a highly heterogeneous and complex tissue with dynamic recruitment and expansion of multiple cell types that interact in multifaceted ways within a localized area. Rheumatoid arthritis synovium has primarily been studied either by immunostaining or by molecular profiling after tissue homogenization. Here, we use Spatial Transcriptomics, where tissue-resident RNA is spatially labeled in situ with barcodes in a transcriptome-wide fashion, to study local tissue interactions at the site of chronic synovial inflammation. We report comprehensive spatial RNA-Seq data coupled to cell type-specific localization patterns at and around organized structures of infiltrating leukocyte cells in the synovium. Combining morphological features and high-throughput spatially resolved transcriptomics may be able to provide higher statistical power and more insights into monitoring disease severity and treatment-specific responses in seropositive and seronegative rheumatoid arthritis.

Lipidome profile predictive of disease evolution and activity in rheumatoid arthritis

Lipid mediators are crucial for the pathogenesis of rheumatoid arthritis (RA); however, global analyses have not been undertaken to systematically define the lipidome underlying the dynamics of disease evolution, activation, and resolution. Here, we performed untargeted lipidomics analysis of synovial fluid and serum from RA patients at different disease activities and clinical phases (preclinical phase to active phase to sustained remission). We found that the lipidome profile in RA joint fluid was severely perturbed and that this correlated with the extent of inflammation and severity of synovitis on ultrasonography. The serum lipidome profile of active RA, albeit less prominent than the synovial lipidome, was also distinguishable from that of RA in the sustained remission phase and from that of noninflammatory osteoarthritis. Of note, the serum lipidome profile at the preclinical phase of RA closely mimicked that of active RA. Specifically, alterations in a set of lysophosphatidylcholine, phosphatidylcholine, ether-linked phosphatidylethanolamine, and sphingomyelin subclasses correlated with RA activity, reflecting treatment responses to anti-rheumatic drugs when monitored serially. Collectively, these results suggest that analysis of lipidome profiles is useful for identifying biomarker candidates that predict the evolution of preclinical to definitive RA and could facilitate the assessment of disease activity and treatment outcomes.

Development of a hyperbranched polymer-based methotrexate nanomedicine for rheumatoid arthritis

Methotrexate (MTX) is an effective disease modifying anti-rheumatic drug, but can cause significant hepatotoxicity and liver failure in some individuals. The goal of this work was to develop a MTX-conjugated hyperbranched polymeric nanoparticle based on oligo(ethylene glycol) methyl ether methacrylate (OEGMA) and examine its ability to selectively deliver MTX to rheumatic joints while sparing the liver. MTX was conjugated to the hyperbranched polymer via a matrix metalloproteinase-13 cleavable peptide linker. Two populations of nanoparticles were produced, with sizes averaging 20 and 200nm. Tri-peptide (FFK)-modified MTX was liberated in the presence of matrix metalloproteinase 13 (MMP-13)and showed 100 to 1000-fold lower antiproliferative capacity in monocytic THP-1 cells compared to unmodified MTX, depending on whether the gamma-carboxylate of MTX was functionalized with O-tert-butyl. Nanoparticles showed prolonged plasma exposure after intravenous injection with a terminal half-life of approximately 1 day, but incomplete (50%) absorption after subcutaneous administration. Nanoparticles selectively accumulated in inflamed joints in a rat model of rheumatoid arthritis and showed less than 5% biodistribution in the liver after 5 days. MTX-OtBu nanoparticles also showed no hepatocellular toxicity at 500 μM MTX equivalents. This work provides support for the further development of OEGMA-based hyperbranched polymers as MTX drug delivery systems for rheumatoid arthritis. Statement of significanceNanomedicines containing covalently conjugated methotrexate offer the potential for selective accumulation of the potent hepatotoxic drug in rheumatic joints and limited liver exposure. One limitation of the high surface presentation of methotrexate on a nanoparticle surface, however, is the potential for enhanced liver uptake. We developed several OEGMA-based hyperbranched polymers containing alpha-carboxyl modified and unmodified methotrexate conjugated via an MMP-13 cleavable hexapeptide linker. The modified methotrexate polymer showed promising in vitro and in vivo behavior warranting further development and optimization as an anti-rheumatic nanomedicine. This work presents a new avenue for further research into the development of hyperbranched polymers for rheumatoid arthritis and suggests interesting approaches that may overcome some limitations associated with the translation of anti-rheumatic nanomedicines into patients.