scholarly journals Managing Osteoporosis and Joint Damage in Patients with Rheumatoid Arthritis: An Overview

2021 ◽  
Vol 10 (6) ◽  
pp. 1241
Author(s):  
Yoshiya Tanaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Damage ◽  
Kinase Inhibitors ◽  
Joint Destruction ◽  
Joint Damage ◽  
Nuclear Factor Κb ◽  
Cartilage Destruction ◽  
Janus Kinase ◽  
Systemic Autoimmune Disease ◽  
And Cartilage

In rheumatoid arthritis, a representative systemic autoimmune disease, immune abnormality and accompanying persistent synovitis cause bone and cartilage destruction and systemic osteoporosis. Biologics targeting tumor necrosis factor, which plays a central role in the inflammatory process, and Janus kinase inhibitors have been introduced in the treatment of rheumatoid arthritis, making clinical remission a realistic treatment goal. These drugs can prevent structural damage to bone and cartilage. In addition, osteoporosis, caused by factors such as menopause, aging, immobility, and glucocorticoid use, can be treated with bisphosphonates and the anti-receptor activator of the nuclear factor-κB ligand antibody. An imbalance in the immune system in rheumatoid arthritis induces an imbalance in bone metabolism. However, osteoporosis and bone and cartilage destruction occur through totally different mechanisms. Understanding the mechanisms underlying osteoporosis and joint destruction in rheumatoid arthritis leads to improved care and the development of new treatments.

Mechanisms of bone and cartilage destruction

2020 ◽  
pp. 85-94
Author(s):  
Ulrike Harre ◽  
Georg Schett
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Cytokines ◽  
Structural Damage ◽  
Current Knowledge ◽  
Joint Destruction ◽  
Cell Types ◽  
Significant Burden ◽  
Repair Mechanisms ◽  
And Cartilage ◽  
Fibroblast Like Synoviocytes

Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is influenced by the immune system. In past decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints, which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of destruction of bone and cartilage in rheumatoid arthritis.

Cartilage and Bone Biomarkers in Rheumatoid Arthritis: Prediction of 10-year Radiographic Progression

2009 ◽  
Vol 36 (2) ◽  
pp. 266-272 ◽  
Author(s):  
SILJE W. SYVERSEN ◽  
GURO L. GOLL ◽  
DÉSIRÉE van der HEIJDE ◽  
ROBERT LANDEWÉ ◽  
PER IVAR GAARDER ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Matrix Protein ◽  
Radiographic Progression ◽  
Joint Destruction ◽  
Nuclear Factor Κb ◽  
Serum Samples ◽  
Human Cartilage ◽  
Radiographic Damage ◽  
Baseline Serum ◽  
And Cartilage

Objective.As current predictors of joint destruction have low specificity, serological biomarkers reflecting bone and cartilage destruction have been proposed as tools in assessing prognosis of rheumatoid arthritis (RA). We examined whether serum concentrations of a panel of biomarkers could predict radiographic progression in patients with RA.Methods.A cohort of 238 patients with RA was followed longitudinally for 10 years with collection of clinical data and serum samples. These analyses focus on the 136 patients with radiographs of the hands available at baseline and at 5 and/or 10 years. Radiographs were scored according to the van der Heijde-modified Sharp score (SHS). Baseline sera were analyzed for receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), human cartilage glycoprotein-39 (YKL-40), C2C, collagen cross-linked C-telopeptide (CTX-I), and cartilage oligomeric matrix protein (COMP). Multivariate linear and logistic regression analyses were used to identify predictors of radiographic progression.Results.Baseline CTX-I levels were higher in progressors [0.41 ng/ml (interquartile range 0.31–0.75)] than in nonprogressors [0.32 ng/ml (IQR 0.21–0.49)], and were independently associated with 10-year change in radiographic damage score [ß = 16.4 (IQR 5.7–27.1)]. We found no association between radiographic progression and baseline serum levels of RANKL, OPG, C2C, YKL-40, or COMP.Conclusion.This longterm followup study of patients with RA indicates a relationship between elevated CTX-I levels in serum and subsequent joint destruction. This association was, however, weak, and our study does not support that serum CTX-I or any of the other tested biomarkers will serve as more useful prognostic markers than current predictors such as anti-cyclic citrullinated peptide, radiographic damage early in the disease course, and signs of inflammation.

scholarly journals P143 The effect of JAK inhibition on the metabolome of neutrophils from patients with rheumatoid arthritis

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_1) ◽  
Author(s):  
Michele Fresneda Alarcon ◽  
Rudi Grosman ◽  
Susama Chokesuwattanaskul ◽  
Marie Phelan ◽  
Helen Louise Wright
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitors ◽  
Cell Signalling ◽  
Joint Damage ◽  
Janus Kinase ◽  
Ros Production ◽  
Healthy Controls ◽  
Amino Acid Synthesis ◽  
Cell Functions ◽  
Significant Difference

Abstract Background/Aims  Janus kinase inhibitors (JAKi) including baricitinib and tofacitinib target the JAK/STAT pathway and are clinically effective in treating rheumatoid arthritis (RA). Neutrophils play a key role in the pathophysiology of RA and their function is directly affected by these drugs as shown by clinical trials of JAKi which report increased infection rates and transient neutropenia during therapy. The aim of this work is to determine difference in the metabolome of neutrophils from healthy controls and patients with RA, and the effect of JAKi on the metabolome of healthy and RA neutrophils. Methods  Neutrophils were isolated from healthy controls (HC) (n = 10) and patients with RA (n = 10 DMARD-naïve, n = 10 Biologics-naive) and pre-incubated with baricitinib, tofacitinib or a pan-JAK inhibitor (all 200ng/mL) for 2h before snap-freezing. Metabolites were extracted by 50:50 v/v AcN:H2O and analysed by 1H NMR spectroscopy using a 700 MHz Avance IIIHD Bruker NMR spectrometer equipped with a TCI cryoprobe. Chenomx, Bruker TopSpin and tameNMR software were used to identify metabolites and process spectra. Statistical analysis and machine learning models were implemented using R and the Mixomics package. Pathway analysis was carried out using Ingenuity (IPA). ROS production in response to 15 min fMLP stimulation was measured using DHR-123 and flow cytometry. Results  At 0h, changes in levels of NADP+, NADPH and hypoxanthine in RA neutrophils indicated increased production of ROS via NADPH oxidase and xanthine oxidase compared to HC. Lower levels of glucose and increased levels of lactic acid also suggested increased glycolysis in RA neutrophils compared to HC. However after 2h incubation with JAKi, a difference in the response to these drugs was observed. 80 metabolites were higher in RA neutrophils compared to HC following 2h JAKi treatment. IPA analysis revealed the metabolites higher in RA neutrophils were involved in NAD biosynthesis, NAD phosphorylation/dephosphorylation, amino acid synthesis and transport, and carbohydrate metabolism. Changes in the levels of NADP+, NADPH and hypoxanthine in RA neutrophils indicate that JAKi inhibit ROS production. We therefore confirmed experimentally that JAKi inhibit ROS production in response to fMLP (p < 0.05). IPA also predicted altered neutrophil cell functions including cell death and cell-to-cell signalling. We previously showed that JAKi did not affect the constitutive rate of neutrophil apoptosis, however JAKi significantly inhibit the delay in apoptosis induced by GM-CSF (p < 0.05). No significant difference in the metabolome was observed when comparing tofacinib-treatment and baricitinib-treatment in either the HC or RA patient group. Conclusion  The metabolome of RA and HC neutrophils is different at baseline. JAKi alter the levels of intracellular metabolites involved in neutrophil activation and ROS production in RA. This may explain, in part, the efficacy of JAKi in decreasing disease activity and joint damage in RA. Disclosure  M. Fresneda Alarcon: None. R. Grosman: None. S. Chokesuwattanaskul: None. M. Phelan: None. H. Wright: None.

scholarly journals Baricitinib inhibits structural joint damage progression in patients with rheumatoid arthritis—a comprehensive review

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Paul Emery ◽  
Patrick Durez ◽  
Axel J. Hueber ◽  
Inmaculada de la Torre ◽  
Esbjörn Larsson ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Radiographic Progression ◽  
Joint Damage ◽  
Janus Kinase ◽  
X Rays ◽  
Phase 3 ◽  
Once Daily ◽  
Positive Effects ◽  
Damage Progression ◽  
Structural Joint

AbstractBaricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab.

scholarly journals Short-term changes on MRI predict long-term changes on radiography in rheumatoid arthritis: an analysis by an OMERACT Task Force of pooled data from four randomised controlled trials

2016 ◽  
Vol 76 (6) ◽  
pp. 992-997 ◽  
Author(s):  
Charles Peterfy ◽  
Vibeke Strand ◽  
Lu Tian ◽  
Mikkel Østergaard ◽  
Ying Lu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Damage ◽  
Randomised Controlled Trials ◽  
Task Force ◽  
Joint Damage ◽  
Controlled Trials ◽  
X Rays ◽  
X Ray ◽  
Pooled Data ◽  
Randomised Controlled

ObjectiveIn rheumatoid arthritis (RA), MRI provides earlier detection of structural damage than radiography (X-ray) and more sensitive detection of intra-articular inflammation than clinical examination. This analysis was designed to evaluate the ability of early MRI findings to predict subsequent structural damage by X-ray.MethodsPooled data from four randomised controlled trials (RCTs) involving 1022 RA hands and wrists in early and established RA were analysed. X-rays were scored using van der Heijde-modified or Genant-modified Sharp methods. MRIs were scored using Outcome Measures in Rheumatology (OMERACT) RA MRI Score (RAMRIS). Data were analysed at the patient level using multivariable logistic regression and receiver operating characteristic curve analyses.ResultsProgression of MRI erosion scores at Weeks 12 and 24 predicted progression of X-ray erosions at Weeks 24 and 52, with areas under the curve (AUCs) of 0.64 and 0.74, respectively. 12-week and 24-week changes in MRI osteitis scores were similarly predictive of 24-week and 52-week X-ray erosion progressions; pooled AUCs were 0.78 and 0.77, respectively. MRI changes in synovitis at Weeks 12 and 24 also predicted progression of X-ray joint damage (erosion and joint-space narrowing) at Weeks 24 and 52 (AUCs=0.72 and 0.65, respectively).ConclusionsEarly changes in joint damage and inflammation detected with MRI predict changes in joint damage evident on subsequent X-rays. These findings support the use of MRI as a valid method for monitoring structural damage in short-duration RCTs.

scholarly journals Fibroblast Like Synovial Cell Subsets in Rheumatoid Arthritis

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.

scholarly journals Peptides Bearing Multiple Post-Translational Modifications as Antigenic Targets for Severe Rheumatoid Arthritis Patients

2021 ◽  
Vol 22 (24) ◽  
pp. 13290
Author(s):  
Cristina García-Moreno ◽  
María J. Gómara ◽  
Raúl Castellanos-Moreira ◽  
Raimon Sanmartí ◽  
Isabel Haro
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Damage ◽  
Serum Antibody ◽  
Joint Damage ◽  
Erosive Disease ◽  
Post Translational Modifications ◽  
Diagnosis And Prognosis ◽  
Modified Peptides ◽  
Chimeric Peptides

Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies that are of paramount importance for the diagnosis and prognosis of the disease and have been implicated in its pathogenesis. Proteins resulting from post-translational modifications (PTMs) are capable of triggering autoimmune responses important for the development of RA. In this work, we investigate serum antibody reactivity in patients with an established RA against a panel of chimeric peptides derived from fibrin and filaggrin proteins and bearing from one to three PTMs (citrullination, carbamylation and acetylation) by home-designed ELISA tests (anti-AMPA autoantibodies). The role of anti-AMPAs as biomarkers linked to the presence of a more severe RA phenotype (erosive disease with radiological structural damage) and to the presence of interstitial lung disease (ILD), a severe extra-articular manifestation in RA patients entailing a high mortality, was also analyzed. In general, the association with the clinical phenotype of RA was confirmed with the different autoantibodies, and especially for IgA and IgM isotypes. The prevalence of severe joint damage was only statistically significant for the IgG isotype when working with the peptide bearing three PTMs. Furthermore, the median titers were significantly higher in patients with RA-ILD, a finding not observed for the IgG isotype when working with the single- and double-modified peptides.

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