Therapeutic Intervention In Rheumatoid Arthritis Research Articles

Inflammatory macrophage reprogramming strategy of fucoidan microneedles-mediated ROS-responsive polymers for rheumatoid arthritis

During the pathogenesis of rheumatoid arthritis, inflammatory cells usually infiltrate synovial tissues, notably, M1-type macrophages, whose redox imbalance leads to the degradation of joint structures and deterioration of function. Natural active products play a vital role in immune modulation and antioxidants. In this study, we constructed a ROS-responsive nanoparticle called FTL@SIN, which consists of fucoidan (Fuc) and luteolin (Lut) connected by a ROS-responsive bond, Thioketal (TK), and encapsulated with an anti-rheumatic drug, Sinomenine (SIN), for synergistic anti-inflammatory effects. The FTL@SIN is then dispersed in high molecular weight Fuc-fabricated dissolvable microneedles (FTL@SIN MNs) for local administration. Therapy of FTL@SIN MNs afforded a significant decrease in macrophage inflammation while decreasing key pro-inflammatory cytokines and repolarizing M1 type to M2 type, thereby ameliorating synovial inflammation, and promoting cartilage repair. Additionally, our investigations have revealed that Fucoidan (Fuc) demonstrates synergistic effects, exhibiting superior mechanical strength and enhanced physical stability when compared to microneedles formulated solely with hyaluronic acid. This study combines nanomedicine with traditional Chinese medicine, a novel drug delivery strategy that presents a promising avenue for therapeutic intervention in rheumatoid arthritis.

Lymphatic vessels: roles and potential therapeutic intervention in rheumatoid arthritis and osteoarthritis.

Lymphatic vessel networks are a main part of the vertebrate cardiovascular system, which participate in various physiological and pathological processes via regulation of fluid transport and immunosurveillance. Targeting lymphatic vessels has become a potent strategy for treating various human diseases. The presence of varying degrees of inflammation in joints of rheumatoid arthritis (RA) and osteoarthritis (OA), characterized by heightened infiltration of inflammatory cells, increased levels of inflammatory factors, and activation of inflammatory signaling pathways, significantly contributes to the disruption of cartilage and bone homeostasis in arthritic conditions. Increasing evidence has demonstrated the pivotal role of lymphatic vessels in maintaining joint homeostasis, with their pathological alterations closely associated with the initiation and progression of inflammatory joint diseases. In this review, we provide a comprehensive overview of the evolving knowledge regarding the structural and functional aspects of lymphatic vessels in the pathogenesis of RA and OA. In addition, we summarized the potential regulatory mechanisms underlying the modulation of lymphatic function in maintaining joint homeostasis during inflammatory conditions, and further discuss the distinctions between RA and OA. Moreover, we describe therapeutic strategies for inflammatory arthritis based on lymphatic vessels, including the promotion of lymphangiogenesis, restoration of proper lymphatic vessel function through anti-inflammatory approaches, enhancement of lymphatic contractility and drainage, and alleviation of congestion within the lymphatic system through the elimination of inflammatory cells. At last, we envisage potential research perspectives and strategies to target lymphatic vessels in treating these inflammatory joint diseases.

PROBIOTICS AS A MECHANISM TO REDUCE INFLAMMATION AND SLOW THE PROGRESSION OF RHEUMATOID ARTHRITIS

Introductions. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and damage to joints, leading to pain and disability. Although the exact cause of RA is unknown, a dysregulated immune response and chronic inflammation are believed to play a key role in the development and progression of the disease. Recently, there has been increasing interest in the potential of probiotics as a therapeutic intervention for RA. Probiotics are live microorganisms that, when consumed in adequate amounts, confer health benefits on the host. In particular, several studies have suggested that probiotics may be able to modulate the immune system and reduce inflammation, potentially slowing the progression of RA.

Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis

ObjectivesImmune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the...

Loss of balance between protective and pro-inflammatory synovial tissue T-cell polyfunctionality predates clinical onset of rheumatoid arthritis

ObjectivesThis study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of...

MiR‑152 inhibits rheumatoid arthritis synovial fibroblast proliferation and induces apoptosis by targeting ADAM10.

miR‑152 has been reported to be downregulated in rheumatoid arthritis (RA). However, the functional significance and molecular mechanisms underlying the role of miR‑152 in RA remain largely unknown. The present study aimed to explore the functional role and the underlying mechanisms of miR‑152 in RA. The expression of miR‑152 in serum, synovial tissues, and fibroblast‑like synoviocytes (FLS) from patients with RA and healthy controls was detected by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). Cell proliferation, cell cycle phase distribution and apoptosis of FLS were measured by Cell Counting Kit‑8 and flow cytometry assays. The effects of miR‑152 on the production of pro‑inflammatory cytokines, including tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, IL‑6 and IL‑8, were examined by ELISA. The target gene of miR‑152 was discovered by miRNA‑target prediction bioinformatics analysis, and confirmed by dual‑luciferase reporter assay, RT‑qPCR and western blotting. Spearman's correlation analysis was performed to assess the relationship between miR‑152 expression and a disintegrin and metalloproteinase domain‑containing protein10 (ADAM10). The results demonstrated that miR‑152 expression levels were significantly decreased in RA serum, synovial tissues and RA‑FLS compared with healthy controls. Overexpression of miR‑152 significantly inhibited cell proliferation, promoted cell apoptosis, and decreased TNF‑α, IL‑1β, IL‑6 and IL‑8 production in RA‑FLS cells. Additionally, ADAM10 was demonstrated to be a target of miR‑152, and expression of the two genes was significantly negatively correlated. Of note, restoration of ADAM10 expression partially reversed the effects of miR‑152 on cell proliferation and apoptosis in RA‑FLS. Thus, miR‑152 may serve as a potential target for therapeutic intervention in RA.

Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis.

Although clinical outcomes for patients with rheumatoid arthritis (RA) have greatly improved with the use of biologic and conventional DMARDs, approximately 40% of patients do not achieve primary clinical outcomes in randomized trials, and only a small proportion achieve lasting remission. Over the past decade, studies in murine models point to the critical role of the lymphatic system in the pathogenesis and therapy of inflammatory-erosive arthritis, presumably by the removal of catabolic factors, cytokines and inflammatory cells from the inflamed synovium. Murine studies demonstrate that lymphatic drainage increases at the onset of inflammatory-erosive arthritis but, as inflammation progresses to a more chronic phase, lymphatic clearance declines and both structural and cellular changes are observed in the draining lymph node. Specifically, chronic damage to the lymphatic vessel from persistent inflammation results in loss of lymphatic vessel contraction followed by lymph node collapse, reduced lymphatic drainage, and ultimately severe synovitis and joint erosion. Notably, clinical pilot studies in patients with RA report lymph node changes following treatment, and thus draining lymphatic vessels and nodes could represent a potential biomarker of arthritis activity and response to therapy. Most importantly, targeting lymphatics represents an innovative strategy for therapeutic intervention for RA.

Acute serum amyloid A is an endogenous TLR2 ligand that mediates inflammatory and angiogenic mechanisms

IntroductionAcute-phase serum amyloid A (A-SAA) has cytokine-like properties and is expressed at sites of inflammation. We examined whether A-SAA-induced pro-inflammatory mechanisms are mediated through Toll-like receptor 2 (TLR2) in rheumatoid...

Anilino-monoindolylmaleimides as potent and selective JAK3 inhibitors

We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.

ADAM15 Adds to Apoptosis Resistance of Synovial Fibroblasts by Modulating Focal Adhesion Kinase Signaling

To study the contribution of ADAM15, a disintegrin metalloproteinase that is up-regulated in the rheumatoid arthritis (RA) synovial membrane, to the characteristic resistance of RA synovial fibroblasts (RASFs) to apoptosis induction by genotoxic stress or stimulation with proapoptotic FasL, which is present at high concentrations in RA synovial fluid. Caspase 3/7 activity and the total apoptosis rate in RASFs upon exposure to the DNA-damaging agent camptothecin or FasL were determined using enzyme assays and annexin V staining. Phosphorylated signaling proteins were analyzed by immunoblotting. RNA interference was used to silence ADAM15 expression. NF-κB activity was determined by enzyme-linked immunosorbent assay. RASFs displayed significantly higher caspase 3/7 activity upon camptothecin and FasL exposure when ADAM15 had been down-regulated by specific small interfering RNAs. Upon FasL stimulation, RASFs phosphorylated focal adhesion kinase (FAK) and c-Src (Src), and activated phosphatidylinositol 3-kinase as well as the transcription factor NF-κB. This ADAM15-dependent, FasL-induced activation of antiapoptotic kinases and NF-κB was demonstrated by a marked reduction of apoptosis upon knockdown of ADAM15 protein expression. Inhibitors specifically interfering with FAK and Src signaling, such as FAK inhibitor 14 and dasatinib, potently induce apoptosis in RASFs, with significant enhancement by the silencing of ADAM15. ADAM15 contributes to apoptosis resistance in RASFs by activating the Src/FAK pathway upon FasL exposure, rendering the FAK/Src signaling pathway an interesting target for potential therapeutic intervention in RA.

Heat shock proteins can be targets of regulatory T cells for therapeutic intervention in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by excessive immune responses resulting in inflammation of the joints. Although current therapies can be successful in dampening inflammation, a long-lived state of tolerance is seldom achieved. Therefore, novel therapies are needed that restore and maintain tolerance in patients with RA. Targeting regulatory T cells (Tregs) is a successful strategy to achieve tolerance, as was shown in studies performed in animal models and in human clinical trials. The antigen-specificity of Tregs is crucial for their effectiveness and allows for very specific targeting of these cells. However, which antigen is suitable for autoimmune diseases such as RA, for which the autoantigens are largely unknown? Heat shock proteins (HSPs) are ubiquitously expressed and can be up-regulated during inflammation. Additionally, HSPs, or HSP-derived peptides are immunogenic and can be recognised by a variety of immune cells, including Tregs. Therefore, this review highlights the potential of HSP-specific Tregs to control inflammatory immune responses. Targeting HSP-specific Tregs in RA can be achieved via the administration of HSPs (derived peptides), thereby controlling inflammatory responses. This makes HSPs attractive candidates for therapeutic intervention in chronic autoimmune diseases, with the ultimate goal of inducing long-lasting tolerance.

SAT0014 Synovial Sublining Macrophages: A Sensitive Biomarker for Response to Treatment in Early RA Patients.

BackgroundThe synovial membrane is the primary site of inflammation in rheumatoid arthritis and as such the study of pathobiological synovial specimens has led to a greater understanding of disease pathogenesis....

Serum Interleukin 6 Before and After Therapy with Tocilizumab Is a Principal Biomarker in Patients with Rheumatoid Arthritis

Biologic treatments including the humanized anti-interleukin 6 (anti-IL-6) receptor antibody tocilizumab (TCZ) provide therapeutic options for patients with rheumatoid arthritis (RA). We investigated useful biomarkers to predict the responsiveness to TCZ by measurement of serum proinflammatory cytokine concentrations. Serum samples were collected from 61 patients with RA before biologic treatment and at 4 weeks after initial administration of either TCZ (n = 32) or infliximab (IFX; n = 29) and from 13 healthy serum donor controls. Disease Activity Score of 28 joints (DAS28) was determined at baseline and after treatment. Although IL-1β, IL-2, IL-6, IL-17A, IL-17F, interferon-α, and tumor necrosis factor-α (TNF-α) were all increased in sera from patients with RA compared with controls, only the IL-6 level was significantly correlated with DAS28 before treatment. The IL-6 level before treatment was positively correlated with DAS28 after TCZ treatment, and was significantly lower in TCZ-responsive patients (as judged by a post-treatment DAS28 < 3.2) than in TCZ-resistant patients (post-treatment DAS28 ≥ 3.2). DAS28 after TCZ was significantly lower than after administration of IFX in patients with low pretreatment IL-6 (< 51.5 pg/ml, the mean baseline value of IL-6 in all RA patients), but not in those with high pretreatment IL-6. These results indicate that low serum IL-6 is associated with a favorable response to TCZ. Although both TNF-α and IL-6 are major targets of therapeutic intervention in RA, baseline serum IL-6 but not baseline TNF-α level is a potential biomarker reflecting disease activity. Measurement of serum IL-6 in RA before treatment may be useful to estimate residual disease activity after TCZ treatment and to predict responsiveness to TCZ treatment.

Early rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic disease characterized by chronic inflammation of the synovial joints damage and loss of the function. The ultimate goal in managing RA is to prevent joint damage and to maintain functional ability. Consequently, early diagnosis and treatment is important, but predictive markers for RA are still confined to autoantibodies and also magnetic resonance imaging (MRI) and sonography do not appear to sufficiently distinguish between early RA and non RA. Evidence shows that substantial and irreversible joint damage already occurs within the first 2 years after disease onset. This "window of opportunity" hypothesis for therapeutic intervention in RA is based on the existence of a time frame within which there is a potential for a greater response to therapy, resulting in sustained benefits or, perhaps most important, a chance of cure. There is increasing evidence for beneficial effects of early DMARDs (disease-modifying anti-rheumatic drugs) therapy over delayed treatment in patients who present with arthritis of recent onset. However, no universal consensus exists concerning the choice of initial drug or whether single drug or combination should be given as initial treatments. Most studies demonstrated superiority of aggressive over conventional approaches. Because the tumor necrosis factor (TNF)-alpha inhibitors have proved to stop joint damage progression in severe progressive RA, the achievement of these agents in early RA are currently of great interest.

The Suitability of Yoga as a Potential Therapeutic Intervention for Rheumatoid Arthritis: A Focus Group approach

The aim of this study was to explore the views of patients with rheumatoid arthritis (RA) regarding the suitability of yoga as a potential therapeutic intervention in the management of RA. Twenty-two participants with RA were recruited from outpatient clinics at a regional hospital in New Zealand and divided into four focus groups. Heterogeneity between groups in terms of age, gender, duration of RA and functional ability provided opinions from a cross-section of RA patients. Transcripts were analysed using thematic analysis, with four themes predominating. Firstly, participants described their experience of symptoms related to their RA in three independent but linked categories of physical, mental and social well-being. Secondly, participants perceived the management of their RA to be prescriptive, medicalized and failing to address their wider health concerns. Thirdly, participants perceived yoga as a safe, adaptable therapy that may allow self-management of their RA. However, there was some concern that functional limitations may inhibit ability to practise the physical aspects of yoga. Fourthly, requirements for a yoga intervention that would be feasible for people with RA were presented by participants. Patients with RA perceive a disparity between their personal experience of living with RA and their current medical management. Yoga is perceived as a potential therapy to address this disparity. Based on opinions expressed by participants, future research regarding a yoga intervention as an adjunctive therapy for managing RA should meet patients' views on feasibility and test outcome measures reflecting the domains of physical, mental and social well-being.

Successful therapy with anti-HMGB1 monoclonal antibodies in two separate experimental arthritis models

Background and objectivesThe nuclear protein HMGB1 (high mobility group chromosomal protein 1) is secreted by activated macrophages/monocytes and promotes inflammation. Extracellular HMGB1 is present in the synovitis of rheumatoid arthritis...

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

Indoleamine 2,3 dioxygenase (IDO) is a catabolic enzyme that initiates the kynurenine pathway of tryptophan degradation and has immunomodulatory properties. The aim of this study was to investigate the regulation of collagen-induced arthritis by tryptophan catabolism mediated by IDO. Arthritis was induced by immunization with type II collagen. After induction of arthritis, the expression of IDO was analyzed by quantitative reverse transcription-polymerase chain reaction. The effect of IDO deficiency on collagen-induced arthritis was assessed in vivo by administration of 1-methyltryptophan and clinical and histologic evaluation of IDO-deficient mice. The requirement for IDO activation was bypassed by administration of L-kynurenine. IDO was induced in lymph node dendritic cells after collagen immunization. Systemic inhibition of tryptophan catabolism during active arthritis increased disease severity. Conversely, bypassing the requirement for tryptophan degradation by the administration of L-kynurenine resulted in amelioration of arthritis. Furthermore, IDO-deficient mice showed a higher incidence of arthritis and exacerbated disease severity compared with IDO-competent mice. Such increased disease activity in IDO-deficient mice correlated early with increased production of the proinflammatory cytokines interferon-gamma and interleukin-17 by lymph node T cells and later with increased infiltration of Th1 and Th17 cells in the inflamed joints. Our data indicate that the induction of IDO controls the accumulation of Th1 and Th17 pathogenic T cells at the site of inflammation during collagen-induced arthritis. Therefore, manipulation of the kynurenine pathway of tryptophan degradation provides the potential for therapeutic intervention in rheumatoid arthritis.

Folate receptor β: a novel target for therapeutic intervention in rheumatoid arthritis?

Folate receptor β: a novel target for therapeutic intervention in rheumatoid arthritis?

Identification of a selective thieno[2,3- c]pyridine inhibitor of COT kinase and TNF-α production

COT (Tpl2 in mice) is a serine/threonine MAP3 kinase that regulates production of TNF-α and other pro-inflammatory cytokines such as IL-1β via the ERK/MAP kinase pathway. As TNF-α and IL-1β are clinically validated targets for therapeutic intervention in rheumatoid arthritis (RA), blocking COT provides a potential avenue for amelioration of disease. Herein we describe identification of a cellular active selective small molecule inhibitor of COT kinase.

Fraktalkine – ein proinflammatorisches Chemokin bei rheumatoider Arthritis

Fractalkine (CX3CL1), so far the only member of the CX3C class of chemokines, and its receptor, CX3CR1, are strongly expressed in the chronically inflamed synovial tissue of patients with rheumatoid arthritis (RA). Due to the specific binding of Fractalkine to its receptor, many proinflammatory reactions involved in the pathogenesis of RA are triggered. Functionally, fractalkine plays an important proinflammatory role in RA pathogenesis as characterized by induction of synovial angiogenesis, chemotaxis, activation of monocytes and T cells as well as the stimulation of proliferation and synthesis of matrix degrading enzymes (matrix metalloproteinases, MMP) in synovial fibroblasts. Fractalkine thus may represent a novel target molecule for therapeutic intervention in RA.