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ID PMID Title PublicationDate abstract
33652029 Roles of leptin on the key effector cells of rheumatoid arthritis. 2021 May Leptin, an adipokine sharing structural characteristics of the long-chain helical cytokine family with the crucial role as a regulator in energy homeostasis, has been paid more and more attention to its immunoregulatory function. Emerging evidence has indicated the roles of leptin on autoimmune diseases such as systemic lupus erythematous (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA) and psoriasis, implying that leptin may be involved in autoimmune disorders. It is very definite that there exists immunocyte dysfunction in RA patients. Growing data has manifested that leptin is increased in both serum and synovial fluid of RA patients compared to healthy controls, suggesting leptin probably takes part in the pathogenesis of RA. The aim of this review is to discuss about what we currently know with regard to the role of leptin in immune system and its effects on RA crucial cells. To clarify the role of leptin in the pathogenesis of RA is beneficial to both the treatment and medical study.
33482191 The role of myeloid-derived suppressor cells in rheumatoid arthritis: An update. 2021 Mar 15 Rheumatoid arthritis (RA) is an autoimmune disease that generally affects the joints. In the late stages of the disease, it can be associated with several complications. Although the exact etiology of RA is unknown, various studies have been performed to understand better the immunological mechanisms involved in the pathogenesis of RA. At the onset of the disease, various immune cells migrate to the joints and increase the recruitment of immune cells to the joints by several immunological mediators such as cytokines and chemokines. The function of specific immune cells in RA is well-established. The shift of immune responses to Th1 or Th17 is one of the most essential factors in the development of RA. Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of myeloid cells, play a regulatory role in the immune system that inhibits T cell activity through several mechanisms. Various studies have been performed on the function of these cells in RA, which in some cases have yielded conflicting results. Therefore, the purpose of this review article is to comprehensively understand the pro-inflammatory and anti-inflammatory functions of MDSCs in the pathogenesis of RA.
32552254 Multiple biomarker approach for the diagnosis and therapy of rheumatoid arthritis. 2021 Jan The lack of specific clinical symptoms for patients in the early stage of rheumatoid arthritis (RA) has created strong interest in the laboratory diagnosis of RA. The main laboratory markers of RA, rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs), can be found in patients with other pathologies and in healthy donors. Even today, there is no single laboratory test that can diagnosis RA with high sensitivity and specificity. To improve the diagnosis and treatment of RA, alternative biomarkers, including 14-3-3η protein, connective tissue growth factor (CTGF), antibodies against PAD4, antibodies against BRAF, and anti-acetylated and anti-carbamylated protein antibodies have been studied extensively. The use of a multiple biomarker approach, the simultaneous measurement of a set of biomarkers, is an alternative strategy for the diagnosis of RA and for predicting the therapeutic effect of biological disease-modifying antirheumatic drugs (DMARDs). However, despite the large number of studies, only a few biomarker combinations have been validated and can be applied in clinical practice. In this article, results of studies focused on the multiple biomarker approach (both multiplex and combined single-analyte assays) to diagnose RA and to predict response to biological drug therapy are reviewed. Additionally, general factors limiting the use of multiplex analysis in RA diagnostics and therapy are discussed.
33503065 Attentional function in fibromyalgia and rheumatoid arthritis. 2021 Concentration difficulties, forgetfulness and mental slowness are common in fibromyalgia syndrome (FMS); initial findings suggest that rheumatoid arthritis (RA) may also be accompanied by cognitive impairments. This study aimed to compare attentional performance between patients with FMS and RA. Attention was quantified in the domains of alerting, orienting and executive control using the Attentional Network Test-Interaction (ANT-I) in 56 women with FMS, 41 women with RA and 50 healthy women. Pain severity was statistically controlled in the group comparison. While FMS patients exhibited longer reaction times and made more errors on the ANT-I than RA patients and healthy women, performance did not differ between RA patients and healthy women. The magnitude of group differences did not vary by the experimental conditions of the ANT-I, suggesting a general attentional deficit in FMS rather than specific impairments in the domains of alerting, orienting and executive control. Differences between patient groups may relate to the different pathogenetic mechanisms involved in the disorders, i.e. inflammatory processes in RA and central nervous sensitization in FMS. In FMS, heightened activity in the pain neuromatrix may interfere with attention, because it requires enhanced neural resources in brain areas that are involved in both pain and attentional processing.
34415206 Role of oxidative stress in pathophysiology of rheumatoid arthritis: insights into NRF2-KE 2021 Nov Rheumatoid arthritis is one of the most prevalent, chronic, inflammatory disorders involving multiple articular and extra-articular complications. Immune deregulation owing to a combinatorial network of cells, inflammatory components, degrading enzymes, angiogenetic factors, exhibiting pleiotropy, synergy, or redundancy, is a critical hallmark for synovial inflammatory milieu reasoning clinical heterogeneity and variability of the disease. As a prototype of autoimmune disease, the pathophysiology of rheumatoid arthritis has been linked to oxidative stress. However, the exact mechanism for these potential driving factors contributing to disease inception and perpetuation is yet elusive. Nuclear factor erythroid 2-related factor 2 - Kelch ECH associating protein 1 (Nrf2-Keap1) pathway, controlled via multifactorial regulation, functions as a ubiquitous, evolutionarily conserved intracellular defense mechanism. Nrf2-Keap1 signalling maintains homeostatic responses against a plethora of environmental or endogenous deviations in cellular growth, death, redox metabolism, inflammation, bone remodelling, detoxification, etc. Administration of antioxidants as an add-on pharmacotherapy along with conventional drugs has been elucidated as a better measure for disease management. Some of the most promising natural and synthetic redox-based therapeutic compounds function as either scavengers of reactive species, or inhibitors of their sources, or activators of an endogenous antioxidant system (Nrf2-Keap1). The present review focuses on the binomial "rheumatoid arthritis-oxidative stress", bringing insights into their pathophysiological interrelationships and Nrf2 signalling, as well as the implications of potential diagnostic oxidative stress biomarkers and therapeutic interventions directed for disease management in patients with rheumatoid arthritis.Highlights:RA has complex etiopathogenesis, evolving from multiple endogenous and exogenous factors with oxidative stress as a critical pathogenic signature.Oxidative damage and damaged compounds could serve as potent biomarkers for disease diagnosis, therapeutic response, and prognosis.One of the supreme cytoprotective signalling cascades, the Nrf2-Keap1 pathway has been known to elicit a protective effect against RA and various other autoimmune, inflammatory, degenerative disorders.Inclusion of natural and synthetic antioxidants has been encouraged by various studies for additional therapy to conventional drugs for better management of the disease.
33557646 Synthesis and anti-rheumatoid arthritis activities of 3-(4-aminophenyl)-coumarin derivativ 2021 Dec Rheumatoid arthritis is a chronic systemic disease characterised by an unknown aetiology of inflammatory synovitis. A large number of studies have shown that synoviocytes show tumour-like dysplasia in the pathological process of RA, and the changes in the expression of related cytokines are closely related to the pathogenesis of RA. In this thesis, a series of novel 3-(4-aminophenyl) coumarins containing different substituents were synthesised to find new coumarin anti-inflammatory drugs for the treatment of rheumatoid arthritis. The results of preliminary activity screening showed that compound 5e had the strongest inhibitory activity on the proliferation of fibroid synovial cells, and it also had inhibitory effect on RA-related cytokines IL-1, IL-6, and TNF-α. The preliminary mechanism study showed that compound 5e could inhibit the activation of NF-κB and MAPKs signal pathway. The anti-inflammatory activity of compound 5e in vivo was further determined in the rat joint inflammation model.
33924481 Joint-Preserving Surgery for Forefoot Deformities in Patients with Rheumatoid Arthritis: A 2021 Apr 13 The combination of first metatarsophalangeal joint arthrodesis and resection arthroplasty of all lesser metatarsal heads has been historically considered the golden standard treatment for rheumatoid forefoot deformities. However, as recent improved management of rheumatoid arthritis have reduced progression of joint destruction, the surgical treatments for rheumatoid forefoot deformities have gradually changed from joint-sacrificing surgery, such as arthrodesis and resection arthroplasty, to joint-preserving surgery. The aim of this literature review was to provide current evidence for joint-preserving surgery for rheumatoid forefoot deformities. We focused on the indications, specific outcomes, and postsurgical complications of joint-preserving surgery in this review.
34220836 The N-Formyl Peptide Receptors and Rheumatoid Arthritis: A Dangerous Liaison or Confusing 2021 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive symmetric inflammation of the joints resulting in bone erosion and cartilage destruction with a progressive loss of function and joint deformity. An increased number of findings support the role of innate immunity in RA: many innate immune mechanisms are responsible for producing several cytokines and chemokines involved in RA pathogenesis, such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6, and IL-1. Pattern recognition receptors (PRRs) play a crucial role in modulating the activity of the innate arm of the immune response. We focused our attention over the years on the expression and functions of a specific class of PRR, namely formyl peptide receptors (FPRs), which exert a key function in both sustaining and resolving the inflammatory response, depending on the context and/or the agonist. We performed a broad review of the data available in the literature on the role of FPRs and their ligands in RA. Furthermore, we queried a publicly available database collecting data from 90 RA patients with different clinic features to evaluate the possible association between FPRs and clinic-pathologic parameters of RA patients.
34238403 One year in review 2021: novelties in the treatment of rheumatoid arthritis. 2021 Jul Management of rheumatoid arthritis (RA) has evolved over the years as a result of better understanding of the role of different therapeutic strategies, as well as following an increasing availability of new disease-modifying antirheumatic drugs. However, the role of patients in sharing decisions, as well as the rules informing precision medicine or the principles to follow in case of specific comorbidities or extra-articular manifestations are still areas for improvement. Moreover, in 2020, the novel Coronavirus disease-19 outbreak has completely changed many attitudes in terms of assessment and treatment paradigms in most clinical diseases, including RA. In this narrative review, the authors report their specific point of view on the management of RA, based on a critical revision of literature published in 2020, focusing on relevant novelties and future research directions.
34645110 Comparing underlying mechanisms of depression in multiple sclerosis and rheumatoid arthrit 2021 Sep 30 Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) are common, chronic, autoimmune diseases affecting many people worldwide. While clinically very different in their phenotype, both diseases are thought to have an autoimmune-mediated origin. MS and RA share genetic similarities, and in both diseases, antibodies against host antigens can be found. Aside from the well-known somatic symptoms, many RA patients also show signs and symptoms of psychiatric illnesses, of which depression is the most common diagnosis. In this commentary, both diseases will be introduced and briefly characterized individually and then compared. Depression will be introduced as one of the most frequent psychiatric diseases in the general population. This paper focuses on presenting the possible causes, including psychosocial factors, genetics, and immunologic mechanisms. Hypotheses aimed to explain the higher incidence of depression in these two seemingly different autoimmune diseases will be discussed.
32967052 Magnetic nanoparticles: A new diagnostic and treatment platform for rheumatoid arthritis. 2021 Feb Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by articular synovitis that eventually leads to the destruction of cartilage and bone in the joints with resulting pain and disability. The current therapies for RA are divided into 4 categories: non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, nonbiological disease-modifying anti-rheumatic drugs (DMARDs), and biological DMARDs. Each drug grouping is beset with significant setbacks that not only include limited drug bioavailability and high clearance, but also varying degrees of drug toxicity to normal tissues. Recently, nanotechnology has provided a promising tool for the development of novel therapeutic and diagnostic systems in the area of malignant and inflammatory diseases. Among these, magnetic nanoparticles (MNPs) have provided an attractive carrier option for delivery of therapeutic agents. Armed with an extra magnetic probe, MNPs are capable of more accurately targeting the local lesion with avoidance of unpleasant systemic side effects. This review aims to provide an introduction to the applications of magnetic nanoparticles in RA, focusing on the latest advances, challenges, and opportunities for future development.
33175968 Is seronegative rheumatoid arthritis true rheumatoid arthritis? A nationwide cohort study. 2021 May 14 OBJECTIVES: The classification of seronegative arthritides can be challenging. Our aim was to examine the incidence of SpA diagnosis among patients initially diagnosed as seronegative RA. METHODS: Using nationwide Finnish registers from social insurance institutions, we identified all adult patients who were diagnosed with incident seronegative RA [International Classification of Diseases (ICD)-10 code M06] from 1 January 2000 to 31 December 2014. The patients whose diagnoses subsequently changed to the ICD-10 codes of SpA (M07, M45, M46, K50 and K51) were identified in the national care register, until 31 December 2016. RESULTS: A total of 9784 adult seronegative RA patients were identified. Of these, 564 patients had their diagnosis subsequently changed to SpA: 275 (48.7%) patients with PsA, 245 (43.4%) patients with axial SpA and 44 (7.8%) patients with diagnoses related to IBD. The cumulative incidence of SpA diagnoses in 15 years was 10.4% (95% CI 8.9, 12.1) and 8.1% (95% CI 7.1, 9.3) in men and women, respectively. CONCLUSION: This study calls for vigilance in seronegative RA patients, especially those with more atypical presentations, since the diagnosis could change. The possibility of SpA diagnosis should be considered and specifically looked for, as this could impact on management and response to treatment.
33301760 The prospects for targeting FcR as a novel therapeutic strategy in rheumatoid arthritis. 2021 Jan Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial membrane hyperplasia, infiltration of inflammatory cells and bone tissue destruction. Although there have been many measures taken for RA therapy in recent years, they are not sufficiently safe or effective. Thus, it is very important to develop new drugs and slow down damage to other healthy organs in the case of RA. Lately, immunoglobulin Fc receptors (FcRs), such as the IgG Fc receptor (FcγR), IgA Fc receptor (FcαR), and IgD Fc receptor (FcδR), have been found to be involved in inducing or suppressing arthritis. FcRs interacting with immune complexes (ICs) are a key factor in the etiopathogenesis of RA. Therefore, an increasing number of methodsfor the targeted treatment of RA with FcRs are emerging, such as recombinant soluble FcγRs, recombinant multimeric Fc fragments and monoclonal antibodies, and have been demonstrated to significantly improve RA symptoms. Simultaneously, certain kinases involved in the downstream signaling of FcRs can also be a target for the treatment of RA, such as Syk and Btk inhibitors. An overview of these FcRs is provided in this review, including a description of FcR-related functions, signaling pathways, and potential FcR-targeting molecules for RA therapy. To date, the initial results of those developed FcR-targeting molecules have been promising. With this, FcRs might offer a better alternative to RA medication. Additionally, further pharmacological characterization and a better understanding of the unique mechanisms of FcR-targeting molecules are necessary.
34213672 Genicular nerve block in rheumatoid arthritis: a randomized clinical trial. 2021 Nov OBJECTIVE: This study highlights the effect of a genicular nerve block (GNB) on pain, function, and inflammation outcome measures in rheumatoid arthritis (RA) knees. METHODS: A total of sixty-four patients diagnosed with RA using ACR/EULAR 2010 criteria with unilateral persistent knee arthritis were recruited to the study. They were randomly assigned into two groups: group 1 received GNB and group 2 received intra-articular triamcinolone. Both groups were examined by the SOLAR scoring system, visual analog scale (VAS), and Lysholm score at 0, 2, and 12 weeks. A semi-quantitative score was used to assess the tenderness and swelling at the same intervals. RESULTS: Function and inflammation improved significantly in group 2 at a 2-week interval as compared to group 1, whereas pain improved in both groups with non-significant differences. After 12 weeks, group 1 showed significant improvement as compared with group 2 for the three outcome measures. Neither the disease activity nor the current medication was related to the GNB effect. Disease duration was negatively related to GNB-induced improvement. CONCLUSION: GNB is a new promising local therapy for RA to control pain, improve function, and alleviate inflammation of the knee joint. Although it has a relatively short-term effect, yet it has outperformed the steroid effect. Key Points • Knee monoarthritis treatment in rheumatoid arthritis is always challenging • GNB has been approved for the treatment of pain in knee osteoarthritis • GNB in this study was able to control active knee arthritis and this effect persisted longer thane intra-articular steroid injection.
33427917 Advances in imaging technologies for the assessment of peripheral neuropathies in rheumato 2021 Mar Peripheral neuropathy in patients with rheumatoid arthritis is associated with a maladaptive autoimmune response that may cause chronic pain and disability. Nerve conduction studies are the routine method performed when rheumatologists presume its presence. However, this approach is invasive, may not reveal subtle malfunctions in the early stages of the disease, and does not expose abnormalities in structures surrounding the nerves and muscles, limiting the possibility of a timely diagnosis. This work aims to present a narrative review of new technologies for the clinical assessment of peripheral neuropathy in Rheumatoid Arthritis. Through a bibliographic search carried out in five repositories, from 1990 to 2020, we identified three technologies that could detect peripheral nerve lesions and perform quantitative evaluations: (1) magnetic resonance neurography, (2) functional magnetic resonance imaging, and (3) high-resolution ultrasonography of peripheral nerves. We found these tools can overcome the main constraints imposed by the previous electrophysiologic methods, enabling early diagnosis.
33673792 Biologics and atherosclerotic cardiovascular risk in rheumatoid arthritis: a review of evi 2021 Apr Introduction: Cardiovascular disease is a leading comorbidity in rheumatoid arthritis. Timely introduction of biologic therapies in a treat-to-target approach has optimized disease-related outcomes and attenuated accrual of comorbidities, including cardiovascular risk.Areas covered: A literature search in MEDLINE (via PubMed) was performed between January 2009 and November 2020. This manuscript explores recent developments in atherosclerotic cardiovascular risk in RA compared with non-RA individuals; it synopsizes differences in vascular function and inflammation, prevalence, burden, vulnerability, and progression of atherosclerotic plaque and their underlying cellular and molecular mechanisms. Finally, it reviews the recent literature on cardioprotective benefits of biologics and draws mechanistic links with inhibition of new plaque formation, stabilization of high-risk lesions and improvement in endothelial function, arterial stiffness, lipid metabolism, and traditional cardiac risk factors.Expert opinion: Increasing evidence points to a solid cardioprotective influence of earlier, longer, and ongoing use of biologic treatments in RA. Nevertheless, the precise mechanistic effects of plaque progression and remodeling, vascular stiffness, endothelial dysfunction, lipid metabolism, and traditional cardiac risk factors are less rigorously characterized.
33670905 The Role of Collagen Triple Helix Repeat-Containing 1 Protein (CTHRC1) in Rheumatoid Arthr 2021 Feb 28 Rheumatoid arthritis (RA) is a chronic autoimmune disease causing inflammation of joints, cartilage destruction and bone erosion. Biomarkers and new drug targets are actively sought and progressed to improve available options for patient treatment. The Collagen Triple Helix Repeat Containing 1 protein (CTHRC1) may have an important role as a biomarker for rheumatoid arthritis, as CTHRC1 protein concentration is significantly elevated in the peripheral blood of rheumatoid arthritis patients compared to osteoarthritis (OA) patients and healthy individuals. CTHRC1 is a secreted glycoprotein that promotes cell migration and has been implicated in arterial tissue-repair processes. Furthermore, high CTHRC1 expression is observed in many types of cancer and is associated with cancer metastasis to the bone and poor patient prognosis. However, the function of CTHRC1 in RA is still largely undefined. The aim of this review is to summarize recent findings on the role of CTHRC1 as a potential biomarker and pathogenic driver of RA progression. We will discuss emerging evidence linking CTHRC1 to the pathogenic behavior of fibroblast-like synoviocytes and to cartilage and bone erosion through modulation of the balance between bone resorption and repair.
33215529 LncRNA GAS5 alleviates rheumatoid arthritis through regulating miR-222-3p/Sirt1 signalling 2021 Feb INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease that affects millions of people. Fibroblast-like synoviocytes (FLSs) located in rheumatoid panni play a pivotal role in the formation of RA. The long noncoding RNA (lncRNA) GAS5 is reportedly downregulated in rheumatoid arthritis. However, its detailed mechanism in RA remains to be explored. This study investigated the roles and related mechanisms of GAS5 in RA. METHODS: The expression levels of GAS5, miR-222-3p, and sirtuin 1 (Sirt1) were evaluated by quantitative PCR (qPCR). Cell proliferation was analyzed by CCK-8 and BrdU assays. Cell apoptosis was assessed by flow cytometry and western blotting. Enzyme-linked immunosorbent assay (ELISA) was utilized to evaluate the levels of TNF-α, IL-1β, and IL-6. The interaction between GAS5 or Sirt1 and miR-222-3p was predicted by starBase and validated by dual-luciferase reporter assay. RESULTS: GAS5 expression was found to be downregulated in the serum samples of RA patients and in RA-FLSs. GAS5 overexpression or the inhibition of miR-222-3p impeded the activity of RA-FLSs by repressing their proliferation and inflammation and by promoting apoptosis. Mechanistically, GAS5 indirectly regulates Sirt1 expression by binding miR-222-3p. Further experiments confirmed that Sirt1 overexpression restored the anti-RA activity of GAS5 under miR-222-3p mimic. CONCLUSIONS: The miR-222-3p/Sirt1 axis was found to be critical for the function of GAS5 in regulating the proliferation, inflammation, and apoptosis of RA-FLSs. These data indicate GAS5 activation as a potential therapeutic strategy for RA progression.
33638167 Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid 2021 Dec Patients with rheumatoid arthritis (RA) are eligible for treatment with therapeutic monoclonal antibodies (mAbs) that target tumor necrosis factor α (TNFα), as well as others, such as rituximab (RTX) and tocilizumab (TCZ). Although pharmacokinetic variability and the link between concentration-clinical response of anti-TNFα mAbs have been well-described, little is known about RTX and TCZ. We aimed to evaluate the variability of RTX and TCZ serum concentrations in RA patients treated in second-line and the relationship between RTX/TCZ concentrations and the clinical response. Serum mAb trough concentrations of RA patients treated with RTX (n = 35) or TCZ (n = 46) were determined at week 24 by liquid chromatography-tandem mass spectrometry. The clinical response was assessed at week 24 by the change in the disease activity score in the 28 joints-erythrocyte sedimentation rate from baseline (ΔDAS28-Erythrocyte Sedimentation Rate) and according to the European League Against Rheumatism (EULAR) recommendations. RTX and TCZ trough concentrations were highly variable, with a coefficient of variation of 171.3% for RTX (median [10th-90th percentiles]: <1.0 µg/mL [<1.0-5.1]) and 132.6% for TCZ (median [10th-90th percentiles]: 5.4 µg/mL [<1.0-27.8]). Univariate analysis did not identify any determinants of such variability, except cotreatment with methotrexate, which was associated with lower RTX concentrations (P = 0.03). The response to treatment was not related to the RTX or TCZ trough concentration. RTX and TCZ trough concentrations at 24 weeks were highly variable in RA patients treated in the second line, without any link concentration-clinical response having been demonstrated.
34592396 Nanotechnology as a promising platform for rheumatoid arthritis management: Diagnosis, tre 2021 Nov 20 Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that develops in about 5 per 1000 people. Over the past years, substantial progresses in knowledge of the disease's pathophysiology, effective diagnosis methods, early detection, and efficient treatment strategies have been made. Notably, nanotechnology has emerged as a game-changer in the efficacious management of many diseases, especially for RA. Joint replacement, photothermal therapy (PTT), photodynamic therapy (PDT), RA diagnosis, and treatment monitoring are nano-based avenues in RA management. Here, we present a brief overview of the pathogenesis of RA, risk factors, conventional diagnostic methods and treatment approaches, and then discuss the role of nanomedicine in RA diagnosis, treatment, and treatment monitoring with an emphasis on functional characteristics distinctive from other RA therapeutics.