scholarly journals Putative Association between Low Baseline Gene Expression in the Peripheral Blood and Clinical Remission in Rheumatoid Arthritis Patients Treated with Tofacitinib

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1385
Author(s):  
Elena V. Tchetina ◽  
Azamat M. Satybaldyev ◽  
Galina A. Markova ◽  
Elena Yu. Samarkina ◽  
Aleksandr M. Lila
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Disease Activity ◽  
Peripheral Blood ◽  
Clinical Remission ◽  
Energy Generation ◽  
Serum Levels ◽  
Das28 Score ◽  
Expression Of Genes ◽  
Before And After

We investigated the importance of the baseline expression of genes involved in energy generation, as prognostic biomarkers of the treatment response to tofacitinib in patients with rheumatoid arthritis (RA). Peripheral blood samples were obtained from 28 patients with RA who received 3 months of tofacitinib therapy from 26 healthy controls. Clinical response was evaluated based on the disease activity score, the erythrocyte sedimentation rate (DAS28-ESR), and the serum levels of ACPA, RF, CRP, and ESR. Clinical remission was assessed based on DAS28 score <2.6. Protein concentrations were measured using ELISA. Total RNA isolated from whole blood was used for gene expression analysis using quantitative RT-PCR. All patients were diagnosed with Steinbrocker’s radiographic stage II-III at baseline, and most showed erosive arthritis with ACPA and RF positivity. Tofacitinib treatment significantly decreased the disease activity. Upon study completion, seven patients showed remission. Before and after TOFA therapy, a significantly higher expression of succinate dehydrogenase and pyruvate kinase genes was observed in all the examined patients compared to healthy subjects. However, the pre-therapy expression of these genes and corresponding proteins was significantly (p ≤ 0.05) lower in patients who showed remission than in other patients with RA. Moreover, we observed that, during follow-up, patients who developed remission showed an increasing trend in the expression of the examined genes, whereas the others showed some decreases in gene expression, although this was not statistically significant. We concluded that, compared with RA patients maintaining persistent moderate or high disease activity, those with clinical remission following tofacitinib treatment showed a significantly lower baseline expression of genes involved in energy generation.

scholarly journals Association between a low baseline level of gene expression of energy metabolism in the blood and the development of clinical remission in response to tofacitinib therapy in patients with rheumatoid arthritis

2021 ◽  
Vol 15 (3) ◽  
pp. 20-26
Author(s):  
E. V. Chetina ◽  
A. M. Satybaldyev ◽  
G. A. Markova ◽  
E. Yu. Samarkina ◽  
M. V. Cherkasova
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Disease Activity ◽  
Peripheral Blood ◽  
Clinical Remission ◽  
Energy Generation ◽  
Janus Kinase ◽  
Control Subjects ◽  
Expression Of Genes ◽  
Lower Baseline

Background. Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by erosive arthritis (synovitis) and systemic inflammation. Janus kinase (JAK) inhibitors (JAKi) are small molecules that block major signal pathways of many cytokines a growth factors, associated with RA. Identification of patients sensitive to JAKi before treatment could significantly improve therapy outcomes. Currently it is not possible to predict JAKi efficacy in every patient, while some patients are non-responsive to the drug, other develop adverse effects. JAKi effect in RA patients has been recently associated with alterations in mitochondrial function and ATP production. Therefore, we hypothesized that baseline metabolic status of RA patients prior to drug administration can predict the therapeutic outcome.Objective: to investigate the predictive value of baseline expression of genes involved in energy generation in the blood of RA patients, for treatment response to JAKi.Patients and methods. We examined peripheral blood of 28 RA patients aged 52.2±15.6 years, average disease duration 3.5 years (range 0.6–19), treated with Tofacitinib (TOFA, 5–10 mg twice a day) during three months and 26 healthy age-matched control subjects. Clinical response was assessed by disease activity score (DAS28-ESR), immunological status by measurements of serum levels of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), and C-reactive protein (CRP). Gene expression was assessed in peripheral blood cells by realtime reverse-transcription polymerase chain reaction (RT-PCR). At baseline all patients had Steinbrocker radiographic stage II–III. Most patients (85.7%) were ACPA and RF positive. Thirteen patients had medium, others – high RA activity.Results and discussion. JAKi treatment significantly decreased the inflammatory disease activity according to DAS28. At the end of the study 17 patients demonstrated moderate disease activity (3.2<DAS28<5.1), 4 patients retained high disease activity while 7, attained remission (DAS28 <2.6). Disease remission, achieved on TOFA treatment, was accompanied by significant decrease in CRP and the number of swollen and tender joints. ESR values were not changed significantly. Gene expression analysis revealed that RA patients, which attained clinical remission after TOFA treatment, demonstrated significantly lower baseline expression of genes associated with glycolysis (pyruvate kinase, PKM2) and oxidative phosphorylation (succinate dehydrogenase, SDHB) compared to other examined RA patients, but higher expression of the abovementioned genes compared to control subjects. Moreover, RA patients who attained clinical remission demonstrated a trend to increase of these gene expressions within follow-up period, while in the rest of patients these gene expression was tending to downregulate.Conclusion. Clinical remission in RA patients treated with JAKi is associated with significantly lower baseline expression of genes associated with energy generation pathways (PKM2 and SDHB) compared to other examined subjects.

scholarly journals Can Rheumatoid factor and Anti-cyclic citrullinated peptides predict true remission in rheumatoid arthritis patients? Study of relationship between autoantibodies levels and muskuloskelatal ultrasound findings in a sample cohort of Egyptian patients in clinical remission

2021 ◽  
Author(s):  
Eman Hassan Al Sayed ◽  
Doaa Shaker Amin
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Rheumatoid Factor ◽  
Clinical Remission ◽  
Power Doppler ◽  
Serum Levels ◽  
Cross Sectional Study ◽  
University Hospital ◽  
Gray Scale ◽  
Cross Sectional

Abstract BackgroundTrue remission is the ultimate goal for rheumatoid arthritis (RA) therapy. Our aim was to investigate the relationship between serum levels of rheumatoid factor (RF) and anti-cyclic citrullinated peptides (Anti-CCP) and ultrasonographic (US) findings in Egyptian RA patients in clinical remission.MethodsUsing data from a cross-sectional study on 50 RA patients in clinical remission or low disease activity (LDA) as defined by disease activity score (DAS28-ESR) cutoff points, performed in Alexandria University Hospital; we analyzed statistical relationships and correlations between RF, Anti-CCP) and Gray Scale (GS) and Power Doppler (PD) US using US7 score. US remission was defined as on a GS ≤ 1 and PD = 0. ResultsAmong 34 patients in clinical remission, 61.8% (21) of patients in clinical remission were in ultrasonographic remission, and 38.2% (13) of patients in clinical remission had subclinical ultrasonographic activity. Patients in clinical remission with US remission had significantly higher Anti-CCP (p= 0.006) but not RF (p= 0.086), than those in clinical remission with US subclinical activity. Anti-CCP positively correlated with synovitis score by power Doppler US (PDUS) (rs= 0.553, p= 0.001), and tenosynovitis/paratenonitis score by gray scale US(GSUS) (rs=0.389, p= 0.023).ConclusionWe demonstrated that patients in clinical RA remission with subclinical US activity had higher serum levels of Anti-CCP, but not RF. Such an association should guide further treatment decisions for those patients.

scholarly journals Metabolic aspects of clinical remission prediction from baseline blood gene expression in patients with rheumatoid arthritis treated with methotrexate

2019 ◽  
Vol 13 (2) ◽  
pp. 47-54
Author(s):  
E. V. Chetina ◽  
N. V. Demidova ◽  
G. A. Markova
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Disease Activity ◽  
Clinical Remission ◽  
Structural Changes ◽  
Caspase 3 ◽  
Unknown Etiology ◽  
Control Group ◽  
Healthy Individuals ◽  
Number Of Patients

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, which is characterized by chronic erosive arthritis (synovitis) and systemic inflammation of the viscera. Methotrexate (MTX) is the drug of choice for RA treatment. However, it is currently impossible to predict the efficacy of MTX in a particular patient; the drug fails to produce the desired effect or causes adverse reactions in a considerable number of patients. The identification of patients who are responsive to MTX could significantly improve the results of therapy.Objective: to investigate the specific features of baseline (pretreatment) expression of genes responsible for major metabolic and energy production pathways in RA patients with different disease activity and to identify the genes, the baseline expression of which could serve as a predictor for remission attainment.Patients and methods. Blood from 40 RA patients (mean age 47.5 years; mean disease duration 7.9 weeks) who had not previously received MTX and 26 healthy donors (mean age 45.1 years). All the patients had used MTX (15 mg/week) for 2 years. Clinical response was evaluated by DAS28 and the serum levels of anti-cyclic citrullinated peptide antibodies, C-reactive protein, and rheumatoid factor. Remission was diagnosed according to ACR/EULAR and DAS28 (DAS28 <2.6). Joint structural changes were radiographically evaluated. Gene expression was determined in peripheral blood cells by real-time reverse transcriptase-polymerase chain reaction. A control group consisted of 26 randomly recruited gender- and sex-matched patients without autoimmune diseases and a family history.Results and discussion. MTX treatment significantly decreased disease activity according to DAS28. At the end of the investigation, the majority of patients had moderate disease activity (3.2≤ DAS28 ≤5.1), 4 had high disease activity, while 12 attained remission (DAS28 <2.6). Gene expression analysis showed that RA patients who had achieved clinical remission after MTX therapy displayed higher baseline expression of the genes associated with glycolysis (Glut1, PKM), inflammation (TNF-α), autophagy (ULK1), apoptosis (caspase 3, p21), and hypoxia (HIF1α), compared with patients who had not attained remission and with healthy individuals. In addition, in patients who had achieved remission, the baseline expression of the CD1 gene was significantly higher than in healthy individuals, while in the remaining patients the expression of this gene was significantly lower than in the controls. While the disease activity remained high, the baseline expression of the p21, caspase 3, TGFβ1, and RUNX2 genes was significantly lower than in healthy individuals and other patients with RA.Conclusion. Remission achievement in RA patients who had not previously received MTX was associated with higher baseline (pretreatment) gene expression associated with glycolytic activity, inflammation, autophagy, apoptosis, and hypoxia compared with patients who failed to attain remission. Elevated baseline expression of the CD1 gene compared with that in healthy individuals may serve as a predictor of sensitivity to MT therapy. 

scholarly journals Correlation analysis between peripheral blood basophils and disease activity in patients with rheumatoid arthritis

2018 ◽  
Vol 16 ◽  
pp. 1721727X1775181
Author(s):  
Na Zhang ◽  
Ze-Ming Zhang ◽  
Xiao-Fei Wang
Keyword(s):  
Rheumatoid Arthritis ◽  
Correlation Analysis ◽  
Disease Activity ◽  
Peripheral Blood ◽  
Disease Assessment ◽  
Absolute Count ◽  
Das28 Score ◽  
Activation Level ◽  
The Absolute ◽  
Monitoring Index

This study set out to investigate the number and the activation of peripheral blood basophils, and the correlation analysis between peripheral blood basophils and disease activity in patients with rheumatoid arthritis (RA). It was determined whether these indices could be used as a monitoring index of RA activation and thereby provide a new disease assessment method for RA. Using flow cytometry, the number and activation level of peripheral blood basophils were determined in RA patients compared with healthy donors. General clinical data were collected and laboratory indices of RA patients were analyzed. A correlation between the number and the activation of basophils was determined using the Disease Activity Score 28 (DAS28), anti-cyclic citrullinated peptide (CCP), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).The absolute count and percentage of peripheral blood basophils in RA patients were significantly lower than that of controls (absolute count P = 0.033, percentage P = 0.047). However, the activation level of basophils was significantly higher than that in controls ( P = 0.034). In addition, the activation level of basophils showed statistically significant differences in disease groups with different activities ( P = 0.011, P = 0.037, and P = 0.002). With an increasing DAS28 score, the number of peripheral blood basophils was shown to decrease while activation level increased. The absolute count and activation level of basophils in RA patients and normal controls on receiver operator characteristic (ROC) curves were (area under the curve (AUC) = 0.676, P = 0.025; AUC = 0.694, P = 0.014), respectively, which were statistically significant in differentiating RA patients from controls. The activation level of basophils was positively correlated with CCP ( P < 0.001, r = 0.831), was positively correlated with CRP ( P = 0.001, r = 0.588). These data are correlated with disease activity assessment and can be used as an early monitoring index of RA activity. Therefore, these studies provide a new basis for evaluation of clinical disease activity in RA patients.

scholarly journals Relation between bone mineral density and IL-17 serum levels in Serbian patients with early Rheumatoid arthritis

Open Medicine ◽  
2014 ◽  
Vol 10 (1) ◽  
Author(s):  
Voja Pavlovic ◽  
Aleksandar Dimic ◽  
Sasa Milenkovic ◽  
Dane Krtinic ◽  
Ivana Aleksic
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Mineral Density ◽  
Disease Activity ◽  
Bone Mineral ◽  
Serum Levels ◽  
Mineral Density ◽  
Serum Samples ◽  
Das28 Score ◽  
Early Ra ◽  
Control Serum

AbstractRheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and destruction of joint cartilage and bone. Different cytokines play important role in the processes that cause articular destruction and extra-articular manifestations in RA. The contribution of cytokines representing the Th1 (INF-γ), Th2 (IL-4) and IL-17A to the pathogenesis of early RA and bone mineral density (BMD) loss in still poorly understood. Serum samples of 38 early RA patients were evaluated for erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), C-reactive protein (CRP), anti-cyclic citrullinated peptide antibodies (anti-CCP) and for the tested cytokines (IL-17A, IL-4 and INF-γ). BMD was evaluated by dualenergyX-ray absorptiometry (DXA). Disease activity score (DAS28) calculation was assessed for all patients. Control serum samples were obtained from 34 healthy volunteers. The levels of tested cytokines were significantly higher (IL-17A, p<0.001; INF-γ, P<0.001; IL-4, P<0.01) in patients with early RA, compared to the healthy controls. In early RA patients, strong correlation of serum IL-17A was found with DAS28, ESR and CRP. Also, a significant negative correlation was found between serum INF-γ levels and the DAS28 score. Significantly positive correlation of BMD values and CRP, DAS28 IL-17A were also demonstrated. DXA analysis revealed that the most common site for osteoporosis was the lumbar spine followed by the femoral neck. BMD values significantly correlated with CRP, DAS28 score and IL-17A serum levels. The mean serum IL-17A levels, in patients with early RA, corresponded with disease activity, severity and BMD loss, indicating the potential usefulness of serum IL-17A in defining the disease activity and bone remodeling.

Molecular Biomarkers of Anti-TNF Response in Patients with Rheumatoid Arthritis

2020 ◽  
Author(s):  
Niyaz Yoosuf ◽  
Mateusz Maciejewski ◽  
Daniel Ziemek ◽  
Scott Jelinsky ◽  
Lasse Folkersen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Flow Cytometry ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Treatment Initiation ◽  
Cell Types ◽  
Proteomics Data ◽  
Peripheral Blood Mononuclear ◽  
Before And After

Abstract BackgroundAdvances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for rheumatoid arthritis (RA) patients. Although treatment specifically targets TNF-α, the downstream mechanisms of immune suppression are not completely understood, and the reason for the reduced efficacy in a significant fraction of patients remains unclear. Hence this study was designed to detect biomarkers and expression signatures of response to TNF inhibition.MethodsIn this study, we included 39 female patients diagnosed with RA who were non-responders to methotrexate treatment. The blood samples were collected before anti-TNF treatment initiation, and three months into treatment. The clinical evaluations were performed based on European League Against Rheumatism (EULAR) and classified 23 patients as responders and 16 as non-responders after three months following the initiation of anti-TNF treatment. We investigated differences in gene expression in peripheral blood mononuclear cells (PBMCs), the proportion of cell types and cell phenotypes in peripheral blood using flow cytometry, the level of proteins in serum, as well as clinical and demographic factors.ResultsWe performed analyses to identify differences between responders and non-responders at both time points (before and after treatment initiation) as well as to detect the changes induced during the treatment using transcriptomics, flow cytometry and proteomics data. The gene expression analysis before treatment revealed notably a higher expression of EPPK1 and BCL6-AS1 in future responders. We further detected suppression of genes and proteins during treatment, most notably a suppression of expression of the gene, T-cell inhibitor CHI3L1 and its protein YKL-40 measured from flow cytometry. We identified an increase in the proportion of T- and B cells, whereas the proportion of granulocytes was suppressed during treatment in responders. Finally, our machine learning models mainly based on transcriptomics data showed high predictive utility (ROC AUC ± SEM: 0.81 ± 0.17) in classifying response before anti-TNF treatment initiation.ConclusionsOur comprehensive analyses resulted in several useful insights regarding the transcriptional and translational regulations of anti-TNF treatment in RA patients. The study reports first transcriptomics analysis using RNA sequencing of isolated PBMCs from anti-TNF naïve and anti-TNF treated RA patients to study biomarkers and predict anti-TNF response.

scholarly journals AB0114 INVESTIGATION OF THE EFFECTS OF EXERCISE ON MIRNA EXPRESSIONS IN PATIENTS WITH RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1086.1-1086
Author(s):  
Z. B. Özcan ◽  
F. S. Karaahmetoğlu ◽  
M. Z. Çiraci ◽  
H. H. Pençe ◽  
M. Vural ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Control Group ◽  
Peripheral Blood Mononuclear ◽  
Sf 36 ◽  
Significant Difference ◽  
Before And After

Background:The goal of treatment for patients with RA is achieve to remission, or at least a state of low disease activity. Exercise is recommended for patients with RA in addition to drug therapy. It has been found to be effective in greatly improving functionality and reducing cardiovascular risk without exacerbating disease activity. Therefore, it is recommended that all RA patients should be encouraged to include aerobic and resistant exercise training as part of their routine treatment (1).miRNAs(miRNA) are known to protect the pathophysiological process specific to RA. miRNA-146a is one of the miRNAs extensively studied in RA, its expression was found to be higher in the synovial fluid and synovial tissue of RA patients compared to healthy individuals (2).Many studies have found that miRNA-146a, along with miRNA-16 and miRNA155 may be related to disease pathology. It has also been found that high levels of miRNA-16 expression correlate with active disease and low levels of expression with inactive disease. It has been found that the increased level of miRNA-155 causes a problem in the modulation of arthritis It has been found that the expression level of miRNA-145 is increased in peripheral blood mononuclear cells of RA patients and synovium supporting osteoclastogenesis (3,4,5).Objectives:It is aimed to investigate the effect of exercise on microRNA expressions in patients with rheumatoid arthritis (RA).Methods:30 patients and 30 healthy controls aged 18-60 years who met the 2010 ACR / EULAR RA criteria were included in the study. A program consisting of strengthening and stretching exercises 2 days a week was applied to the study group for 8 weeks. One day a week, 30 minutes of mild moderate walking was requested. Of the cases at the beginning and at the end of the treatment; 5-10 cc peripheral blood samples were taken into one EDTA tube. Then Numeric Rating Scale (NRS) was used for pain, 28-joint Disease Activity Score (DAS28) was used to calculate disease activity, Health Assessment Questionnaire (HAQ) was used to assess general health and Short Form-36 (SF-36) was used to evaluate quality of life. 5-10 cc peripheral blood samples were taken to only 1 EDTA tube of the control group. In the samples taken, gene expressions of miRNA-146a, miRNA-155, miRNA-16, miRNA-145 were determined by real-time PZR method.Results:There was a significant difference in DAS28, SF-36, NRS, HAQ scales before and after treatment in the RA group of patients (p 0.05). The expression level of MiRNA-146a does not differ significantly before and after treatment (p> 0.05). However, these two groups differ significantly with the control group (p 0.05). No significant difference was observed in the miRNA-155 and miRNA-16 expression levels in the pretreatment, posttreatment, and control groups (p> 0.05).Conclusion:Exercise therapy has a good effect on pain, disease activity, quality of life and general health in patients with RA. It has been found that exercise can affect vii some of the miRNAs involved in disease pathogenesis. However, more comprehensive studies are needed.References:[1]Cooney JK, Law RJ, Matschke V, Lemmey AB, Moore JP, Ahmad Y, et al. Benefits of exercise in rheumatoid arthritis. Journal of Aging Research. 2011. p. 14.[2]Abou-Zeid A, Saad M, Soliman E. MicroRNA 146a expression in rheumatoid arthritis: Association with tumor necrosis factor-alpha and disease activity. Genet Test Mol Biomarkers. 2011;15(11):807–12.[3]Murata K, Yoshitomi H, Tanida S, Ishikawa M, Nishitani K, Ito H, et al. Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 2010;12(3):86.[4]Pauley KM, Satoh M, Chan AL, Bubb MR, Reeves WH, Chan EKL. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res Ther. 2008;10(4):101.[5]Evangelatos G, Fragoulis GE, Koulouri V, Lambrou GI. Micrornas in rheumatoid arthritis: From pathogenesis to clinical impact. Autoimmun Rev. 2019;18(11):102391.Disclosure of Interests:None declared

Sign in / Sign up

Export Citation Format

Share Document