Choline kinase inhibition in rheumatoid arthritis

ObjectivesLittle is known about targeting the metabolome in non-cancer conditions. Choline kinase (ChoKα), an essential enzyme for phosphatidylcholine biosynthesis, is required for cell proliferation and has been implicated in cancer invasiveness. Aggressive behaviour of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) led us to evaluate whether this metabolic pathway could play a role in RA FLS function and joint damage.MethodsCholine metabolic profile of FLS cells was determined by 1H magnetic resonance spectroscopy (1HMRS) under conditions of ChoKα inhibition. FLS function was evaluated using the ChoKα inhibitor MN58b (IC50=4.2 μM). For arthritis experiments, mice were injected with K/BxN sera. MN58b (3 mg/kg) was injected daily intraperitoneal beginning on day 0 or day 4 after serum administration.ResultsThe enzyme is expressed in synovial tissue and in cultured RA FLS. Tumour necrosis factor (TNF) and platelet-derived growth factor (PDGF) stimulation increased ChoKα expression and levels of phosphocholine in FLS measured by Western Blot (WB) and metabolomic studies of choline-containing compounds in cultured RA FLS extracts respectively, suggesting activation of this pathway in RA synovial environment. A ChoKα inhibitor also suppressed the behaviour of cultured FLS, including cell migration and resistance to apoptosis, which might contribute to cartilage destruction in RA. In a passive K/BxN arthritis model, pharmacologic ChoKα inhibition significantly decreased arthritis in pretreatment protocols as well as in established disease.ConclusionsThese data suggest that ChoKα inhibition could be an effective strategy in inflammatory arthritis. It also suggests that targeting the metabolome can be a new treatment strategy in non-cancer conditions.

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

Journal of Clinical Medicine ◽

10.3390/jcm10061241 ◽

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.

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Role of joint damage, malalignment and inflammation in articular tenderness in rheumatoid arthritis, psoriatic arthritis and osteoarthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-218744 ◽

2021 ◽

pp. annrheumdis-2020-218744

Author(s):

Irina Gessl ◽

Mihaela Popescu ◽

Victoria Schimpl ◽

Gabriela Supp ◽

Thomas Deimel ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Psoriatic Arthritis ◽

Power Doppler ◽

Joint Damage ◽

Joint Space ◽

Early Arthritis ◽

Damage Score ◽

Established Disease ◽

Active Inflammation

ObjectivesTo determine whether clinical tenderness can be considered a sign of inflammatory joint activity in patients with rheumatoid arthritis (RA), osteoarthritis (OA) or psoriatic arthritis (PsA) and to assess other possible factors associated with tenderness.MethodsPatients diagnosed with RA, PsA and OA underwent clinical and ultrasound examination of wrists and finger joints. Radiographs of the hands were scored for erosions, joint space narrowing (JSN), osteophytes and malalignment. A binary damage score (positive if ≥1 erosion, JSN and/or presence of malalignment) was calculated. Differences in grey scale signs of synovitis and power Doppler (PD) between tender non-swollen (TNS) versus non-tender non-swollen (NTNS) joints were calculated. Disease duration was assessed,<2 years was regarded as early and >5 years as long-standing arthritis.ResultsIn total, 34 patients (9 early and 14 long-standing) from patients with RA, 31 patients (7 early and 15 long-standing) with PsA and 30 with OA were included. We found equal frequencies of PD signal between TNS and NTNS joints in RA (p=0.18), PsA (p=0.59) or OA (p=0.96). However, PD had a significant association with tenderness in early arthritis both in RA (p=0.02) and in PsA (p=0.02). The radiographic damage score showed significant association with tenderness in RA (p<0.01), PsA (p<0.01) and OA (p=0.04).ConclusionTenderness might not always be a sign of active inflammation in RA, PsA and OA. While tenderness in early arthritis may be more related to inflammation, established disease is better explained by joint damage and malalignment.

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Update on the Pathomechanism, Diagnosis, and Treatment Options for Rheumatoid Arthritis

Cells ◽

10.3390/cells9040880 ◽

2020 ◽

Vol 9 (4) ◽

pp. 880 ◽

Cited By ~ 10

Author(s):

Yen-Ju Lin ◽

Martina Anzaghe ◽

Stefan Schülke

Keyword(s):

Rheumatoid Arthritis ◽

Side Effects ◽

Bone Erosion ◽

Treatment Options ◽

Joint Damage ◽

Cartilage Destruction ◽

Biologic Dmards ◽

Clinical Benefits ◽

Synthetic Dmards ◽

Inability To Work

Rheumatoid arthritis (RA) is an autoimmune disease that involves multiple joints bilaterally. It is characterized by an inflammation of the tendon (tenosynovitis) resulting in both cartilage destruction and bone erosion. While until the 1990s RA frequently resulted in disability, inability to work, and increased mortality, newer treatment options have made RA a manageable disease. Here, great progress has been made in the development of disease-modifying anti-rheumatic drugs (DMARDs) which target inflammation and thereby prevent further joint damage. The available DMARDs are subdivided into (1) conventional synthetic DMARDs (methotrexate, hydrochloroquine, and sulfadiazine), (2) targeted synthetic DMARDs (pan-JAK- and JAK1/2-inhibitors), and (3) biologic DMARDs (tumor necrosis factor (TNF)-α inhibitors, TNF-receptor (R) inhibitors, IL-6 inhibitors, IL-6R inhibitors, B cell depleting antibodies, and inhibitors of co-stimulatory molecules). While DMARDs have repeatedly demonstrated the potential to greatly improve disease symptoms and prevent disease progression in RA patients, they are associated with considerable side-effects and high financial costs. This review summarizes our current understanding of the underlying pathomechanism, diagnosis of RA, as well as the mode of action, clinical benefits, and side-effects of the currently available DMARDs.

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Magnetic resonance imaging in rheumatoid arthritis

Oxford Textbook of Rheumatoid Arthritis ◽

10.1093/med/9780198831433.003.0019 ◽

2020 ◽

pp. 207-218

Author(s):

Mikkel Østergaard ◽

Philip G. Conaghan ◽

Charles Peterfy

Keyword(s):

Rheumatoid Arthritis ◽

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Soft Tissue ◽

Joint Damage ◽

Resonance Imaging ◽

Established Disease ◽

Tissue Changes ◽

Magnetic Resonance Imaging Mri ◽

Soft Tissue Changes

In rheumatoid arthritis (RA), early diagnosis combined with early initiation of appropriate therapy and tight control of inflammation have been recognized as essential for optimal clinical outcomes. Conventional radiography, though able to detect structural joint damage in patients with established disease, is not sensitive in detecting early disease manifestations such as soft tissue changes and bone damage at its earliest stages. Magnetic resonance imaging (MRI) allows multiplanar tomographic imaging of the body in any plane without geometric distortions associated with projectional techniques, such as radiography, and no ionizing radiation is used. Early bone involvement and inflammatory soft tissue changes of synovitis and tenosynovitis, which are not detectable by conventional clinical, biochemical, and radiographic methods, can be directly visualized and evaluated in detail by MRI. MRI is an increasingly available sensitive technique which has documented utility in the diagnosis, monitoring, and prognostication of patients with RA, and important new knowledge and technical improvements are continuously being acquired.

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Contribution of Multiplex Immunoassays to Rheumatoid Arthritis Management: From Biomarker Discovery to Personalized Medicine

Journal of Personalized Medicine ◽

10.3390/jpm10040202 ◽

2020 ◽

Vol 10 (4) ◽

pp. 202

Author(s):

Carlos M. Laborde ◽

Patricia Castro-Santos ◽

Roberto Díaz-Peña

Keyword(s):

Rheumatoid Arthritis ◽

Personalized Medicine ◽

Physical Disability ◽

Functional Disability ◽

Biomarker Discovery ◽

Joint Damage ◽

Cartilage Destruction ◽

Local Inflammation ◽

Protein Biomarkers ◽

Low Sensitivity

Rheumatoid arthritis (RA) is a multifactorial, inflammatory and progressive autoimmune disease that affects approximately 1% of the population worldwide. RA primarily involves the joints and causes local inflammation and cartilage destruction. Immediate and effective therapies are crucial to control inflammation and prevent deterioration, functional disability and unfavourable progression in RA patients. Thus, early diagnosis is critical to prevent joint damage and physical disability, increasing the chance of achieving remission. A large number of biomarkers have been investigated in RA, although only a few have made it through the discovery and validation phases and reached the clinic. The single biomarker approach mostly used in clinical laboratories is not sufficiently accurate due to its low sensitivity and specificity. Multiplex immunoassays could provide a more complete picture of the disease and the pathways involved. In this review, we discuss the latest proposed protein biomarkers and the advantages of using protein panels for the clinical management of RA. Simultaneous analysis of multiple proteins could yield biomarker signatures of RA subtypes to enable patients to benefit from personalized medicine.

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Cartilage proteoglycan aggrecan as a predictor of joint damage in juvenile rheumatoid arthritis

Eastern Mediterranean Health Journal ◽

10.26719/2001.7.6.992 ◽

2001 ◽

Vol 7 (06) ◽

pp. 992-1003

Author(s):

Z. A. El Sayed ◽

M. T. Saleh ◽

A. S. Al Wakkad ◽

L. S. Sherief ◽

A. M. Nasr El Din

Keyword(s):

Rheumatoid Arthritis ◽

Juvenile Rheumatoid Arthritis ◽

Joint Damage ◽

Vascular Diseases ◽

Cartilage Destruction ◽

Healthy Children ◽

Significant Drop ◽

Baseline Serum ◽

Collagen Vascular Diseases ◽

Active Inflammation

Aggrecan was measured in the sera of 31 children with juvenile rheumatoid arthritis and in the synovial fluid of 10 of them. Patients were evaluated at baseline and 3 months later. Radiographs were repeated also after 1 year. As comparison, 15 apparently healthy children with no disease and 10 children with arthritis due to other collagen vascular diseases were studied. Baseline serum aggrecan was significantly higher in juvenile rheumatoid arthritis patients compared to controls and other patients. On re-evaluation, a significant drop in serum aggrecan from baseline values coincided with a significant drop in clinical and laboratory indices of active inflammation. Serum aggrecan can help to assess the extent of cartilage destruction and is useful as a prognostic tool to predict joint damage in patients with juvenile rheumatoid arthritis.

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ADVANCED TREATMENT IN RHEUMATOID ARTHRITIS. IS IT POSSIBLE TO TAPER THE BIOLOGICAL TREATMENT?

Romanian Journal of Rheumatology ◽

10.37897/rjr.2015.4.1 ◽

2015 ◽

Vol 24 (4) ◽

pp. 189-193

Author(s):

Ina Cambu ◽

◽

Catalina Raluca Nuta ◽

Denisa Predeteanu ◽

◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Functional Outcomes ◽

Biological Treatment ◽

Biological Therapy ◽

Cartilage Destruction ◽

Biological Agents ◽

Systemic Autoimmune Disease ◽

Sustained Remission ◽

Combined Use ◽

New Treatment

Rheumatoid arthritis (RA) is a systemic autoimmune disease, leading to synovial hypertrophy and adjacent bone and cartilage destruction. The combined use of biological agents and methotrexate (MTX) has revolutionised the treatment of RA producing significant improvements in clinical, radiographic and functional outcomes. The results of clinical study and experience of the specialities of rheumatology in clinical statement showed the long treatment may be associated with side effects, in addition biological treatment means high cost. The next goal should be remission without the use of biological agents. That’s why new treatment in RA means the tapering or even stopping the biological treatment in patients with RA who reached remission. In association with the new recommendation EULAR in 2013 there are many studies which showed the possibility of tapering or discontinuing the biological therapy in patients in sustained remission.

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Anti-Inflammatory Effects of TRAF-Interacting Protein in Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Mediators of Inflammation ◽

10.1155/2016/3906108 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 7

Author(s):

Qing-Zhu Kong ◽

Li-Tao Guo ◽

Jia-Ning Yang ◽

Yan-Fei Wang ◽

Jing-Xin Zhao ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Proinflammatory Cytokines ◽

Transforming Growth Factor ◽

Proteolytic Enzymes ◽

Joint Damage ◽

Cartilage Destruction ◽

Interacting Protein ◽

Systemic Inflammatory Disease ◽

Anti Inflammatory ◽

Fibroblast Like Synoviocytes

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by inflammatory cell infiltration, synovial inflammation, and cartilage destruction. Proliferative fibroblast-like synoviocytes (FLS) play crucial roles in both propagation of inflammation and joint damage because of their production of great amount of proinflammatory cytokines and proteolytic enzymes. In this study, we investigate the role of TRAF-interacting protein (TRIP) in regulating inflammatory process in RA-FLS. TRIP expression was attenuated in RA-FLS compared with osteoarthritis- (OA-) FLS. Overexpression of TRIP significantly inhibited the activation of NF-κB signaling and decreased the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) in TNFα-stimulated RA-FLS. Furthermore, TRIP was found to interact with transforming growth factorβ-activated kinase 1 (TAK1) and promoting K48-linked polyubiquitination of TAK1 in RA-FLS. Our results demonstrate that TRIP has anti-inflammatory effects on RA-FLS and suggest TRIP as a potential therapeutic target for human RA.

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Biomarkers for the diagnosis and treatment of rheumatoid arthritis-a systematic review

10.22541/au.162184194.49768862/v1 ◽

2021 ◽

Author(s):

dima abdelhafiz ◽

Tara Baker ◽

Alice galscow

Keyword(s):

Rheumatoid Arthritis ◽

Systematic Review ◽

Disease Activity ◽

Bone Erosion ◽

English Literature ◽

Joint Damage ◽

Cartilage Destruction ◽

Diagnosis And Treatment ◽

Pre Treatment ◽

One Year

Background Rheumatoid Arthritis (RA) is an autoimmune disease, symmetrically affecting the small joints. Biomarkers are tools that can be used in the diagnosis and monitoring of RA. Aim To systematically explore the role of the biomarkers: C-reactive protein (CRP), Rheumatoid factor (RF), Anti-cyclic citrullinated protein (Anti-CCP), 14-3-3η and the multi-biomarker disease activity (MBDA) score for the diagnosis and treatment of RA. Methods A systematic review of the English literature using four different databases was carried out. Results CRP>7.1 mg/L predicted poor conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) outcome in RA. Anti-CCP, CRP ≥0.3 mg/dL and RF predicted bone erosion and cartilage destruction. Combination of high 14-3-3η with RF and CRP improved the prediction of rapid erosion progression (REP). Anti-CCP was not associated with disease activity, but was associated with increased radiographic damage (r=0.46, p=0.048). RF was not associated with joint damage but correlated with ultrasound-detected bone erosion. 14-3-3η significantly correlated with inflammation, bone remodelling and osteoporosis in RA patients (p<0.05). 14 3 3η positively correlated with RA duration (p=0.003), disease activity and positive RF (P=0.025) and it distinguished early from established RA. Early MBDA scores correlated with later response in disease activity, after 6 and 12 weeks of treatment (p<0.05). MBDA score was able to differentiate between small differences in disease activity and predicted remission over one year period. Conclusion The investigated biomarkers are helpful tools in clinical practice for diagnosis, monitoring of treatment and predicting prognosis in RA patients. However, further research is still required to investigate novel biomarkers for the pre-treatment selection of potentially responsive patients before starting therapy for a precision medicine in this area.

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