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 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.

Anti-carbamylated Protein Antibodies and Serum Level of 14-3-3 Protein for Early Detection of Rheumatoid Arthritis Patient in Correlation with Rheumatoid Factor, Anti-CCP Antibodies, Disease Activity and Joint Damage using High Frequency Musculoskeletal Ultrasound

2020 ◽  
Vol 7 (2) ◽  
pp. 141-153
Author(s):  
Sahar A. Ahmed ◽  
Enas M. Darwish ◽  
Walaa A. Attya ◽  
Mai Samir ◽  
Mennatallah Elsayed ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Rheumatoid Factor ◽  
Disease Activity Score ◽  
Joint Damage ◽  
Musculoskeletal Ultrasound ◽  
Activity Score ◽  
Das 28 ◽  
Significant Difference ◽  
Hands And Feet

Background: Rheumatoid arthritis (RA) is a common progressive chronic inflammatory autoimmune disease which affects mostly small joints, causing pain, swelling, deformity, and disability. Although progress has been made in exploring RA nature, still there is a lot to know about the disease pathogenesis, diagnosis, and treatment. Aim of the Work: To investigate the role of serum anti-carbamylated protein antibodies and 14-3-3η in the diagnosis of RA compared to rheumatoid factor (RF), anti-CCP antibodies, and highfrequency musculoskeletal ultrasound used to assess the disease activity and joint damage. Methods: Serum anti-carbamylated protein antibodies and 14-3-3η were measured using ELISA in 61 RA patients and 26 normal controls. RA Disease Activity Score (DAS 28), X-ray and musculoskeletal ultrasound (hands and feet), carotid ultrasound (Intima-Media Thickness IMT) were used in assessing the RA disease. Results: Anti-carbamylated protein antibodies were significantly elevated in RA patients 4.5 (4.1- 8.9 U⁄ml) compared to the control 3.2(1.9- 4.3 U⁄ml) (p< 0.001) but 14-3-3η showed no significant difference. There was a significant positive correlation between anti-carbamylated protein antibodies, 14-3-3η levels and disease activity score assessed by DAS 28, increased IMT measured by carotid duplex, total synovitis and total erosion score were assessed by musculoskeletal ultrasound. There was no correlation between RF and anti-CCP antibodies. Anti-carbamylated protein antibodies were found to have 66.7% sensitivity and 85.2% specificity in RA diagnosis, while 14- 3-3η had 51.9% sensitivity and 72.1% specificity. Conclusion: Anti-carbamylated protein antibodies and 14-3-3η have a high sensitivity and specificity in RA diagnosis and had a correlation with the disease activity and joint damage.

scholarly journals Effect of janus kinase inhibitors and methotrexate combination on malignancy in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vinod Solipuram ◽  
Akhila Mohan ◽  
Roshniben Patel ◽  
Ruoning Ni
Keyword(s):  
Rheumatoid Arthritis ◽  
Combination Therapy ◽  
Randomized Controlled Trials ◽  
Random Effect ◽  
Janus Kinase ◽  
Controlled Trials ◽  
Randomized Controlled ◽  
Increased Risk ◽  
Significant Difference ◽  
Risk Of Malignancy

Abstract Background Rheumatoid arthritis (RA) is a systemic autoimmune disease. The combination therapy of methotrexate (MTX) and Janus kinase inhibitor (JAKi) is commonly used. Patients with RA are at increased risk of malignancy, however, it remains unclear whether the combination therapy is associated with a higher risk. Objective To assess the malignancy risk among patients with RA receiving combination therapy of JAKi and MTX compared to MTX alone. Methods PubMed, Cochrane and Embase were thoroughly searched for randomized controlled trials (RCTs) in patients with RA receiving JAKi and MTX, from inception to July 2020. Primary endpoints were malignancy events, Non melanomatous skin cancer (NMSC) and malignancy excluding NMSC and secondary endpoints were serious adverse events (SAE), deaths. Risk ratio (RR) and 95% CI were calculated using the Mantel–Haenszel random-effect method. Results 659 publications were screened and 13 RCTs with a total of 6911 patients were included in the analysis. There was no statistically significant difference in malignancy [RR = 1.42; 95% CI (0.59, 3.41)], neither NMSC [RR = 1.44 (0.36, 5.76)] nor malignancies excluding NMSC [RR = 1.12 (0.40, 3.13)]. No statistically significant difference between the two groups for SAE [RR = 1.15 (0.90, 1.47)] and deaths [RR = 1.99 (0.75, 5.27)] was found. Conclusion The adjunction of JAKi to MTX is not associated with an increased risk of malignancy when compared to MTX alone. There is no increased risk of SAE and deaths when compared to MTX alone in patients with RA.

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 Interleukin-37 as an anti-inflammatory cytokine: does its relation to disease activity suggest its potential role in rheumatoid arthritis therapy?

2021 ◽  
Vol 48 (1) ◽  
Author(s):  
Eman A. Baraka ◽  
Mona G. Balata ◽  
Shereen H. Ahmed ◽  
Afaf F. Khamis ◽  
Enas A. Elattar
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Cross Sectional Study ◽  
Healthy Controls ◽  
Tender Joint ◽  
Cross Sectional ◽  
Reactive Protein ◽  
Significant Difference ◽  
The Mean ◽  
Anti Inflammatory

Abstract Background This study aimed to measure the serum and synovial interleukin (IL)-37 levels in rheumatoid arthritis (RA) patients compared to patients with primary knee osteoarthritis (PKOA) and healthy controls and to detect its relation to RA disease activity. Results This cross-sectional study included 50 RA patients with a mean age of 40.24 ± 8.62 years, 50 patients with PKOA with a mean age of 56.69 ± 4.21, and 40 healthy controls with a mean age of 41.75 ± 7.38 years. The mean serum IL-37 level in the RA patients (382.6 ± 73.97 pg/ml) was statistically significantly (P < 0.001) the highest among the studied groups; however, it showed a non-significant difference between the PKOA patients (70.38 ± 27.49 pg/ml) and the healthy controls (69.97 ± 25.12 pg/ml) (P > 0.94). Both serum and synovial IL-37 levels were significantly positively correlated with disease activity scores (r = 0.92, P< 0.001 and r = 0.85, P < 0.001), tender joint counts (r = 0.83, P < 0.001 and r = 0.82, P < 0.001 ), swollen joint counts (r = 0.72, P < 0.001 and r = 0.60, P < 0.001), visual analog scale (r = 0.82, P < 0.001 and r = 0.82, P < 0.001), erythrocyte sedimentation rate (r = 0.75, P < 0.001 and r = 0.65, P < 0.001), and C-reactive protein (r = 0.93, P < 0.001 and r = 0.79, P < 0.001), respectively. Conclusion Serum and synovial IL-37 were significantly elevated in the RA patients, and they were closely correlated. Being less invasive, the serum IL-37 could be a marker of disease activity and could reflect the effective disease control by drugs. Having an anti-inflammatory effect could not suggest IL-37 as the key player to control inflammation alone, but its combination with other anti-proinflammatory cytokines could be investigated.

scholarly journals Rheumatoid arthritis synovial fluid neutrophils drive inflammation through production of chemokines, reactive oxygen species and neutrophil extracellular traps

2020 ◽  
Author(s):  
Helen L Wright ◽  
Max Lyon ◽  
Elinor A Chapman ◽  
Robert J Moots ◽  
Steven W Edwards
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Neutrophil Migration ◽  
Joint Damage ◽  
Inflammatory Disorder ◽  
Ros Production ◽  
Chronic Inflammatory Disorder ◽  
Adaptive Immune Cells ◽  
Activated Neutrophils ◽  
Healthy Control

Rheumatoid arthritis (RA) is a chronic inflammatory disorder affecting synovial joints. Neutrophils are believed to play an important role in both the initiation and progression of RA, and large numbers of activated neutrophils are found within both synovial fluid (SF) and synovial tissue from RA joints. In this study we analysed paired blood and SF neutrophils from patients with severe, active RA (DAS28>5.1, n=3) using RNA-seq. 772 genes were significantly different between blood and SF neutrophils. IPA analysis predicted that SF neutrophils had increased expression of chemokines and ROS production, delayed apoptosis, and activation of signalling cascades regulating the production of NETs. This activated phenotype was confirmed experimentally by incubating healthy control neutrophils in cell-free RA SF, which was able to delay apoptosis and induce ROS production in both unprimed and TNFα primed neutrophils (p<0.05). RA SF significantly increased neutrophil migration through 3μM transwell chambers (p<0.05) and also increased production of NETs by healthy control neutrophils, including exposure of myeloperoxidase (MPO) and citrullinated histone-H3-positive DNA NETs. IPA analysis predicted NET production was mediated by signalling networks including AKT, RAF1, SRC and NF-κB. Our results expand the understanding of the molecular changes that take place in the neutrophil transcriptome during migration into inflamed joints in RA, and the altered phenotype in RA SF neutrophils. Specifically, RA SF neutrophils lose their migratory properties, residing within the joint to generate signals that promote joint damage, as well as inflammation via recruitment and activation of both innate and adaptive immune cells. We propose that this activated SF neutrophil phenotype contributes to the chronic inflammation and progressive damage to cartilage and bone observed in patients with RA.

scholarly journals Serum total adenosine deaminase activity in Nepalese patients with Rheumatoid Arthritis

2013 ◽  
Vol 4 (2) ◽  
pp. 30-35
Author(s):  
N Gautam ◽  
J Archana ◽  
R Kumar ◽  
LI Singh ◽  
RM Sapkota ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adenosine Deaminase ◽  
Healthy Controls ◽  
Medical Sciences ◽  
Potential Marker ◽  
Diagnostic Potential ◽  
Clinical Scenarios ◽  
Adenosine Deaminase Activity ◽  
Significant Difference ◽  
Reliable Marker

Objective: Several studies indicate that serum adenosine deaminase (ADA) activity could be a potential marker for the diagnosis of patients with rheumatoid arthritis (RA). However, there has been no such study that could independently verify this finding in Nepali population. The present study therefore aims to measure the total ADA activity in the sera of Nepalese RA patients and verify its diagnostic potential. Materials and Methods: A total of 69 RA patients who visited Universal College of Medical Sciences Teaching Hospital (UCMSTH), Bhairahawa, Nepal for their medical treatment were enrolled for this study. An equal number of age and sex-matched healthy controls were also included in the study. Blood samples were collected from each study subjects and analyzed for serum total ADA, Creactive protein (CRP) and rheumatoid factor (RF). Results: Serum total ADA activity was found to be significantly (p<0.0001) higher (30.0 }10.1 U/L) in all RA patients compared to healthy controls (13.5 } 3.6 U/L). However, no significant difference (p>0.05) in the ADA activity was found between the smokers and non-smoker RA patients. Out of total 69 RA patients, only 16 (23.1%) were positive for CRP and 11 (15.9%) were positive for RF. Conclusion: Measurement of serum total ADA activity could be a reliable marker for the diagnosis of RA in Nepali population with relevant clinical scenarios when there is absence of CRP and RF in the serum.  DOI: http://dx.doi.org/10.3126/ajms.v4i2.6208 Asian Journal of Medical Sciences 4(2013) 30-35

scholarly journals Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in RA Patients?

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Przemyslaw J. Kotyla
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Metabolism ◽  
Theoretical Background ◽  
Janus Kinase ◽  
Biologically Active ◽  
System Functioning ◽  
And Function

The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response. JAK kinase blockade offers a unique opportunity to block most of the key cytokines enabling the deep interaction into immune system functioning. Following discovery first Jakinibs were intensively studied in various forms of autoimmune diseases, including rheumatoid arthritis, and finally two Jakinibs tofacitinib and Baricitinib have been approved for the treatment of rheumatoid arthritis. Some clinical data indicated that under special circumstances Jakinibs may be even superior to biologics in the treatment of RA; however this suggestion should be verified in large clinical and observational studies.

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