Physical disability in rheumatoid arthritis is associated with cartilage damage rather than bone destruction

Background:In rheumatoid arthritis (RA), irreversible physical disability appears to be more clearly associated with cartilage damage rather than with bone erosions (BE) using conventional radiography (CR) imaging.Objectives:To investigate the correlation between the ultrasound (US) and CR findings indicative of joint damage and irreversible physical disability in patients with RA in sustained clinical remission.Methods:Patients in sustained clinical remission according to the Simplified Disease Activity Index (SDAI)≤3.3 for at least 6 months were enrolled. The following data were regireted: age, disease duration, anti-cyclic citrullinated peptide (ACPA) antibody and rheumatoid factor (RF) status, Health Assessment Questionnaire (HAQ), CR of hands and feet [evaluated using the Simple Erosion Narrowing Score (SENS) method]. A standardized US examination was carried out to investigate the presence of BE (lateral side of II metacarpophalangeal, V metacarpophalangeal and V metatarsophalangeal joints and ulnar styloid) and of cartilage damage (II to V metacarpal heads), bilaterally. BE and cartilage damage were assessed according to OMERACT definitions. A semiquantitative scoring system for both BE (1) and cartilage damage (2) was adopted.Results:Ninety patients were consecutively enrolled. Average time for US evaluation was 10±2 minutes. Both SENS-JSN and US score of cartilage damage (US-CD) were significantly associated with irreversible disability (R=0.39, p<0.01 and R=0.46, p<0.01). US and CR showed a moderate agreement in the evaluation of cartilage damage (kappa=0.52, 95% confidence interval: 0.44-0.61).Figure 1.shows the association between disability and structural damage (A: US-CD, B: US-BE, C: SENS-JSN and D: SENS-BE). After adjusting for confounding factors (age, disease duration, ACPA and RF status, SENS-BE and US-BE) cartilage damage was the only significant predictor of irreversible disability both using CR (R2=0.31, adjusted R2=0.26, standardized β=0.36, p<0.01) and US (R2=0.31, adjusted R2=0.26, standardized β=0.34, p<0.01).Conclusion:This study supports the hypothesis that cartilage damage is more relevant than BE in determining irreversible disability in RA. Our data provide further evidence in favor of the external validity of US in the assessment of cartilage damage.References:[1] Ohrndorf S, Messerschmidt J, Reiche BE, et al. Evaluation of a new erosion score by musculoskeletal ultrasound in patients with rheumatoid arthritis: is US ready for a new erosion score? Clin Rheumatol. 2014;33:1255-62.[2] Mandl P, Studenic P, Filippucci E, et al. Development of semiquantitative ultrasound scoring system to assess cartilage in rheumatoid arthritis. Rheumatology (Oxford). 2019;58:1802-11.Disclosure of Interests:Edoardo Cipolletta: None declared, Antonella Incorvaia: None declared, Riccardo Mashadi Mirza: None declared, Andrea Di Matteo Grant/research support from: the publication was conducted while Dr. Di Matteo was an ARTICULUM fellow, Marika Tardella: None declared, Walter Grassi Speakers bureau: Prof. Grassi reports personal fees from AbbVie, personal fees from Celgene, personal fees from Grünenthal, personal fees from Pfizer, personal fees from Union Chimique Belge Pharma, outside the submitted work., Emilio Filippucci Speakers bureau: Dr. Filippucci reports personal fees from AbbVie, personal fees from Bristol-Myers Squibb, personal fees from Celgene, personal fees from Roche, personal fees from Union Chimique Belge Pharma, personal fees from Pfizer, outside the submitted work.

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Pyridinone Derivatives as Interesting Formyl Peptide Receptor (FPR) Agonists for the Treatment of Rheumatoid Arthritis

Molecules ◽

10.3390/molecules26216583 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6583

Author(s):

Letizia Crocetti ◽

Claudia Vergelli ◽

Gabriella Guerrini ◽

Maria Paola Giovannoni ◽

Liliya N. Kirpotina ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cartilage Damage ◽

Bone Destruction ◽

Joint Inflammation ◽

Chronic Inflammatory Disease ◽

New Drugs ◽

Formyl Peptide Receptor ◽

Pyridine Derivative ◽

Pharmacological Tests ◽

Formyl Peptide

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint inflammation, cartilage damage and bone destruction. Although the pharmacological treatment of RA has evolved over the last few years, the new drugs have serious side effects and are very expensive. Thus, the research has been directed in recent years towards new possible targets. Among these targets, N-formyl peptide receptors (FPRs) are of particular interest. Recently, the mixed FPR1/FPR2 agonist Cpd43, the FPR2 agonist AT-01-KG, and the pyridine derivative AMC3 have been shown to be effective in RA animal models. As an extension of this research, we report here a new series of pyridinone derivatives containing the (substituted)phenyl acetamide chain, which was found to be essential for activity, but with different substitutions at position 5 of the scaffold. The biological results were also supported by molecular modeling studies and additional pharmacological tests on AMC3 have been performed in a rat model of RA, by repeating the treatments of the animals with 10 mg/kg/day of compound by 1 week.

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The Impact of Proinflammatory Cytokynes of Rheumatoid Polyarthritis on the Generalized Loss of Bone Mass

Revista de Chimie ◽

10.37358/rc.18.9.6572 ◽

2018 ◽

Vol 69 (9) ◽

pp. 2541-2545

Author(s):

Raluca Barzoi ◽

Elena Rezus ◽

Codruta Badescu ◽

Razan Al Namat ◽

Manuela Ciocoiu

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Nuclear Factor ◽

Receptor Activator ◽

Level Function ◽

Rheumatoid Polyarthritis ◽

The Impact ◽

Nuclear Factor Kb

There is a bidirectional interaction between most immune cells and osteoblasts, osteoclasts and their precursor cells. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) system plays an essential role in the formation of osteoblasts, but it also has implications in osteoclast biology and implicitly on the diseases characterized by bone loss. Proinflammatory cytokines existing at synovial level function as direct or indirect stimulators of osteoclast differentiation, but also of its survival or activity, although some cytokines may also play an antiosteocastogenic role. The fate of bone destruction is determined by the balance between osteoclastogenic and antiosteoclastogenic mediators. Our study has shown that the early initiation of the therapy with anti-TNF and anti-IL6 biological agents, in patients with rheumatoid arthritis, inhibits bone destruction, regardless of the anti-inflammatory activity in patients with rheumatoid arthritis.

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Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice

Arthritis Research & Therapy ◽

10.1186/s13075-019-2073-x ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 5

Author(s):

Scott A. Scarneo ◽

Liesl S. Eibschutz ◽

Phillip J. Bendele ◽

Kelly W. Yang ◽

Juliane Totzke ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Bone Resorption ◽

Bone Formation ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Inflammatory Diseases ◽

Cartilage Damage ◽

Cytokine Signaling ◽

Periosteal Bone Formation ◽

Bone Width

Abstract Objectives To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. Methods Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). Results Here, we show takinib’s ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t½ = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. Conclusion Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.

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POS0393 FIBRIN DEPOSITION IS AN ACTIVE TRIGGER OF CARTILAGE DEGENERATION IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2521 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 426.1-426

Author(s):

T. Hügle ◽

S. Nasi ◽

D. Ehirchiou ◽

P. Omoumi ◽

A. So ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cartilage Damage ◽

Cartilage Degeneration ◽

Cartilage Explants ◽

Fibrin Deposition ◽

Qrt Pcr ◽

Catabolic Genes ◽

Key Factor ◽

Calcific Deposits

Background:Fibrin(ogen) maintains inflammation in various disorders but has never been linked to cartilage damage in rheumatoid arthritis (RA) or other forms of inflammatory arthritis.Objectives:To investigate the role of fibrin deposition on cartilage integrity in arthritis.Methods:Fibrin deposition on knee cartilage was analyzed by immunohistochemistry in RA patients and in murine adjuvant-induced arthritis (AIA). In chondrocytes, fibrinogen expression (Fgα, Fgβ, Fgγ) and procoagulant activity were evaluated by qRT-PCR and turbidimetry respectively. Fibrin-induced catabolic genes were assessed by qRT-PCR in chondrocytes. Fibrin-mediated chondro-synovial adhesion (CSA) with subsequent cartilage tears was studied in co-cultures of human RA cartilage with autologous synoviocytes, in the AIA model, and by MRI. The link between fibrin and calcification was examined in human RA cartilage stained for calcific deposits and in vitro in fibrinogen-stimulated chondrocytes.Results:Fibrin deposition on cartilage correlated with the severity of cartilage damage in human RA explants and in AIA wildtype (WT) mice, while fibrinogen deficient (Fg-/-) mice were protected. Accordingly, fibrin upregulated catabolic enzymes (Adamts5 and Mmp13) in chondrocytes. Secondly, CSA was present in fibrin-rich and damaged cartilage in AIA WT but not in Fg-/- mice. In line, autologous human synoviocytes, cultured on RA cartilage explants, adhered exclusively to fibrin-positive degraded areas. Gadolinium-enhanced MRI of human joints showed contrast-enhancement along cartilage surface in RA patients but not in controls. Finally, fibrin co-localized with calcification in human RA cartilage and triggered chondrocyte mineralization inducing pro-calcification genes (Anx5, Pit1, Pc1) and cytokine (IL-6). Although at a much lesser extent, we observed similar fibrin-mediated mechanisms in osteoarthritis (OA).Conclusion:Fibrin deposition directly impacts on cartilage integrity via induction of catabolism, mechanical stress, and calcification. Potentially, fibrin is a key factor of cartilage damage occurring in RA as a secondary consequence of inflammation.Disclosure of Interests:None declared

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FRI0127 Suppression of radiographic progression after gradual methotrexate tapering in patients with rheumatoid arthritis patients maintaining low disease activity - Prospective multicenter study-

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1415 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 645.1-645

Author(s):

K. Katayama ◽

K. Yujiro ◽

T. Okubo ◽

R. Fukai ◽

T. Sato ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Joint Destruction ◽

Reduction Rate ◽

Bone Destruction ◽

High Response ◽

Continuation Rate ◽

Low Disease Activity ◽

One Year ◽

Response Group

Background:Many studies have been reported to reduce/discontinue Biologics in the treatment of rheumatoid arthritis (RA). In contrast, study for tapering methotrexate (MTX) has been limited (1,2).Objectives:We prospectively examined whether bone destruction will progress at 48 weeks after tapering or discontinuing MTX (UMIN000028875).Methods:The subjects were RA patients who have maintained low disease activity or lower for 24 weeks or more in DAS28-CRP after MTX administration. Patients having PDUS Grade 2 or 3 per site by bilateral hand ultrasonography (26 area) were excluded in this study owing to risk for joint destruction. The joint destruction was evaluated by the joint X-ray evaluation by modified total Sharp scoring (mTSS) at 1 year after the start of tapering MTX. Evaluation of clinical disease activities, severe adverse events, the continuation rate during MTX tapering were also evaluated. According to tapering response, prognostic factor for good response for tapering, joint destruction was determined. Predictors for successful tapering MTX and progression of bone destruction were determined. Statistical analysis was performed by t-test or Wilcoxon rank sum test using SAS .13.2 software.Results:The subjects were 79 (16 males, 63 females). Age average 60.9 years, disease duration 4 years 4 months, MTX dose 8.43 mg / w, DAS28-CRP 1.52, DMARDs (24.3%), ACPA 192.7 U / ml (70.5%), RF 55.6 IU / ml (65.4%).MTX was tapered from an average of 8.43 mg / w before study to 5.46 mg / w one year later. In the treatment evaluation, DAS28-CRP increased from 1.52 to 1.84. 89.7% of subjects did not progress joint damage. Other disease activities significantly increased (Table 1). The one-year continuation rate was 78.2%. Since tapering effects were varied widely, we divided patients into three groups; Flared group (N=14, initial MTX dose 8.71mg/w, final MTX dose 8.42mg/w), Low response group (N=31, final MTX reduction rate< 50%, initial MTX dose 8.93mg/w, final MTX dose 6.22mg/w), High response group (N=34, final MTX reduction rate≥ 50%, initial MTX dose 8.5mg/w, final MTX dose 3.15mg/w)(Table 2).Higher RF value at baseline and higher MTX dose at 3M, 6M were predictors of whether a subject was in Low response group or High Response group. Higher RF value and mTSS at baseline and higher MTX dose at 6M were predictors whether a subject was in Flared group or High response group. Lower age was predictor of whether a subject was in Flared group or Low responder group. Finally, mean ΔmTSS /y in Flared group (0.36) was not significantly higher than in low response group (0.07) and in high response group (0.01).Table 1Table 2.Predictors for successful tapering MTX and progression of bone destructionConclusion:Patients with MTX-administered low disease activity and finger joint echo PDUS grade 1 satisfy almost no joint destruction even after MTX reduction. For tapering, predictors may be helpful for maintaining patient’s satisfaction.References:[1]Baker KF, Skelton AJ, Lendrem DW et al. Predicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study. J. Autoimmunity. 2019;105: 102298.[2]Lillegraven S, Sundlisater N, Aga A et al. Tapering of Conventional Synthetic Disease Modifying Anti-Rheumatic Drugs in Rheumatoid Arthritis Patients in Sustained Remission: Results from a Randomized Controlled Trial. American College of Rheumatology. 2019; Abstract L08.Disclosure of Interests:None declared

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From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms22020686 ◽

2021 ◽

Vol 22 (2) ◽

pp. 686

Author(s):

Chao-Yi Wu ◽

Huang-Yu Yang ◽

Shue-Fen Luo ◽

Jenn-Haung Lai

Keyword(s):

Rheumatoid Arthritis ◽

Treatment Options ◽

Clinical Manifestations ◽

Bone Destruction ◽

Response To Therapy ◽

Current Evidence ◽

Prognosis Prediction ◽

Diagnosis And Prognosis ◽

Systemic Inflammatory Disease ◽

Citrullinated Protein

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

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Total Flavonoids of Bidens pilosa Ameliorates Bone Destruction in Collagen-Induced Arthritis

Planta Medica ◽

10.1055/a-1352-5124 ◽

2021 ◽

Author(s):

Mengqin Hong ◽

Xingyu Fan ◽

Shengxiang Liang ◽

Wang Xiang ◽

Liting Chen ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Proinflammatory Cytokines ◽

Bone Destruction ◽

Nuclear Factor Κb ◽

Total Flavonoids ◽

Nuclear Factor ◽

Collagen Induced Arthritis ◽

Bidens Pilosa ◽

X Ray ◽

Receptor Activator

AbstractRheumatoid arthritis is a chronic autoimmune disease characterized by the infiltration of synovial inflammatory cells and progressive joint destruction. Total flavonoids of Bidens pilosa have been used against inflammation in rheumatoid arthritis, but its role in bone destruction remains to be explored. The aim of this paper was to study whether total flavonoids of B. pilosa relieve the severity of collagen-induced arthritis in rats, particularly whether it regulates the production of proinflammatory cytokines and the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin signaling pathway. In this research, a collagen-induced disease model was induced in adult rats by subcutaneous injection of collagen II. Total flavonoids of B. pilosa at different doses (40, 80, and 160 mg/kg/d) were administered intragastrically, while methotrexate (1 mg/kg/w) was injected intraperitoneally as a positive control. Paw swelling, arthritis score, and body weight were assessed and evaluated. The severity of joint damage was determined using X-ray and confirmed by histopathology. The expression levels of receptor activator of nuclear factor-κB ligand, osteoprotegerin, IL-1β, IL-17, and TNF in the serum and tissue were assayed using ELISA and immunohistochemistry. We found that total flavonoids of B. pilosa attenuated collagen-induced arthritis at the macroscopic level, and total flavonoids of B. pilosa-treated rats showed reduced paw swelling, arthritis scores, and X-ray appearance of collagen-induced arthritis in addition to improved histopathological results. These findings were consistent with reduced serum and tissue receptor activator of nuclear factor-κB ligand, TNF, IL-1β, and IL-17 levels but increased osteoprotegerin levels. Our data suggest that total flavonoids of B. pilosa attenuate collagen-induced arthritis by suppressing the receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB/osteoprotegerin pathway and the subsequent production of proinflammatory cytokines. In addition, total flavonoids of B. pilosa may be a promising therapeutic candidate for the management of rheumatoid arthritis.

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N6-Methyladenosine and Rheumatoid Arthritis: A Comprehensive Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.731842 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sha Wu ◽

Xiao-Feng Li ◽

Yuan-Yuan Wu ◽

Su-Qin Yin ◽

Cheng Huang ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Myeloid Leukemia ◽

Immune Cell ◽

Bone Destruction ◽

Synovial Cell ◽

Biological Processes ◽

Cell Life ◽

History Of ◽

The Relationship

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by immune cell infiltration, fibroblast-like synovial cell hyperproliferation, and cartilage and bone destruction. To date, numerous studies have demonstrated that immune cells are one of the key targets for the treatment of RA. N6-methyladenosine (m6A) is the most common internal modification to eukaryotic mRNA, which is involved in the splicing, stability, export, and degradation of RNA metabolism. m6A methylated-related genes are divided into writers, erasers, and readers, and they are critical for the regulation of cell life. They play a significant role in various biological processes, such as virus replication and cell differentiation by controlling gene expression. Furthermore, a growing number of studies have indicated that m6A is associated with the occurrence of numerous diseases, such as lung cancer, bladder cancer, gastric cancer, acute myeloid leukemia, and hepatocellular carcinoma. In this review, we summarize the history of m6A research and recent progress on RA research concerning m6A enzymes. The relationship between m6A enzymes, immune cells, and RA suggests that m6A modification offers evidence for the pathogenesis of RA, which will help in the development of new therapies for RA.

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Fibroblast Like Synovial Cell Subsets in Rheumatoid Arthritis

10.5772/intechopen.99240 ◽

2021 ◽

Author(s):

Søren Lomholt ◽

Morten A. Nielsen ◽

Maithri P. Aspari ◽

Peter B. Jørgensen ◽

Adam P. Croft ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cartilage Damage ◽

Joint Destruction ◽

Human Leukocyte ◽

Synovial Cell ◽

Joint Inflammation ◽

Nuclear Factor Κb ◽

Sequencing Studies ◽

Sublining Layer ◽

Lymphoid Structures

Fibroblasts like synoviocytes (FLS) play several significant roles in rheumatoid arthritis (RA) pathophysiology. This chapter will describe known roles of FLS in disease initiation, joint inflammation, disease persistence and joint destruction. It will describe the newly characterized subsets of FLS based on single cell RNA sequencing studies, and their association to specific aspects of the disease. Finally, we will discuss the future of targeting FLS in the treatment of RA. The FLS in the synovial lining layer are identified by surface complement decay-accelerating factor (CD55) along with lubricin and metallopeptidase expression. Pathological activation of this lining layer subset result in bone and cartilage damage in mice. FLS of the sublining layer are often characterized by THY1 expression, but recent studies have highlighted a heterogeneity where several distinct subsets are identified by additional markers. Sublining FLS expressing human leukocyte antigen-DRA (HLA-DRA) produce C-X-C motif chemokine 12 (CXCL12) and receptor activator of nuclear factor-κB ligand (RANKL) and seems to constitute a pro-inflammatory subset that is associated with inflammation and tertiary lymphoid structures. Another subset of FLS characterized by CD34 expression may discriminate a common progenitor fibroblast subset. Taken together, studies isolating and characterizing gene expression in synovial FLS report both associations of unknown importance and markers that may impose protective or destructive features. This supports evidence of FLS as active players in RA pathology capable of cellular recruitment, local cellular crosstalk and promotion of joint destruction. These discoveries may serve as an atlas for synovial activation in RA and have identified several potential fibroblast markers for the development of targeted treatment.

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