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

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.

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Investigating the Validity of the Minimal Disease Activity State for Patients with Rheumatoid Arthritis Treated with Abatacept

The Journal of Rheumatology ◽

10.3899/jrheum.080059 ◽

2009 ◽

Vol 36 (2) ◽

pp. 260-265 ◽

Cited By ~ 4

Author(s):

GEORGE A. WELLS ◽

MAARTEN BOERS ◽

TRACY LI ◽

PETER S. TUGWELL

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Health Assessment ◽

Control Group ◽

Minimal Disease Activity ◽

The Core ◽

Core Set ◽

Number Of Patients ◽

Minimal Disease ◽

Activity State

Objective.To validate the definitions of minimal disease activity (MDA) in patients with rheumatoid arthritis (RA) and to compare abatacept to control with respect to patients attaining a state of MDA.Methods.Two randomized controlled trials comparing abatacept to control in patients with RA were considered: ATTAIN and AIM. Core set measures, Disease Activity Score 28-joint count (DAS28), and, for AIM, radiographic scores were available. The core set and DAS-based definitions for MDA were calculated and the number of patients in the treatment groups meeting the definitions was compared to determine sensitivity of the criteria to treatment differences and patient severity. The number of times achieving MDA was compared to the change in Health Assessment Questionnaire (HAQ), and for the AIM study compared to change in radiographic scores.Results.For both definitions of MDA, the change in radiographic scores showed a continual decrease in progression the more often a patient was in MDA. The change in HAQ, for both studies, showed a similar consistent improvement — the longer a patient was in MDA, then the better the HAQ score. Significantly more patients in the abatacept group met the core set and DAS-based definition of MDA than in the control group.Conclusion.The presence and persistence of MDA was associated with slowing of radiographic progression and improvement in the HAQ, providing support for discriminative and predictive validity of the measure. The MDA results were consistent with other efficacy analyses indicating a treatment advantage for abatacept.

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P-450 Effects of rheumatoid arthritis and methotrexate therapy on ovarian reserve in infertile women

Human Reproduction ◽

10.1093/humrep/deab127.007 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

G Vlasova ◽

S Perminova

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Ovarian Reserve ◽

Small Sample Size ◽

Genetic Material ◽

Main Group ◽

Small Sample ◽

Control Group ◽

Proliferating Cells ◽

Number Of Patients

Abstract Study question Do patients with infertility and rheumatoid arthritis (RA) treated with methotrexate (MTX) have ovarian reserve alterations? Summary answer Women with infertility and RA treated with MTX were found to have statistically significant decrease of ovarian reserve. What is known already Rheumatoid arthritis (RA) is one of the most prominent inflammatory diseases affecting women of child-bearing age [Brouwer J. et al, 2014]. RA and its treatment may interfere with the female reproductive physiology. The vast majority of patients with RA are treated with methotrexate (MTX) which is a folate antagonist that inhibits DNA synthesis. MTX, which is the anchor drug in RA, targets actively proliferating cells including the oocytes and granulosa cells which may impair the ovarian reserve [Min Tun Kyaw et al, 2020]. Study design, size, duration A prospective case-control study that enrolled 72 female patients with infertility was conducted in the 2-year time period of September 2018 to October 2020. Participants/materials, setting, methods The main group comprised 32 patients with infertility and RA; the control group consisted of 40 women with infertility only. Patients with RA were stratified into subgroups based on whether or not they received MTX. To investigate ovarian reserve measurement of serum anti-Müllerian hormone (AMH) was used. The level of AMH was evaluated concerning RA duration and activity, as well as the age at initiation of MTX therapy, dosage, and treatment duration. Main results and the role of chance The mean age of the study population was 36±3 years. The duration of RA was 4 [3;11] years. The low disease activity based on DAS28-ESR (disease activity score based on 28 joints using the erythrocyte sedimentation rate) prevailed(56.2%). In the main group 19(59.4%) women received MTX therapy. The MTX dosage was 15 [15;20]mg /wk, the duration of MTX therapy by the day of inclusion in the study was 18.7[1;15]months. The AMH level was significantly lower in the main group (2.1 n /ml vs 2.73ng /ml, p = 0.043). The number of patients with decreased ovarian reserve (AMH level<1.0ng/ml) significantly prevailed in the group of patients with RA (25% vs 5%, p = 0.015). When assessing the AMH level in patients with RA who received MTX (n = 19) and patients in the control group, there was a tendency towards a decrease in the indicator in the first subgroup, but no statistically difference was found (p = 0.074). Correlation analysis of the dependence of AMH level on the patient age showed the most significant decrease in AMH in the patients with RA receiving MTX compared to the patients with RA who did not, and compared to all patients with RA regardless of the therapy received (rs=-0.563)(p < 0.05). Limitations, reasons for caution The lack of statistically significant data in certain cases may be due to the small sample size. Wider implications of the findings RA and MTX administration are associated with a significant decrease in AMH levels. The age of initiation of the therapy is negatively correlated with the AMH level. In this regard, patients with already compromised reproductive function who are planning to receive MTX should be advised to preserve the genetic material. Trial registration number 567890

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AB0226 EVALUATION OF RITUXIMAB EFFICACY WITH VARIOUS COMPOSITE MEASURES OF INFLAMMATORY ACTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2354 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1139.1-1139

Author(s):

Y. Olyunin ◽

D. Kusevich ◽

E. Nasonov

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

High Activity ◽

Inflammatory Activity ◽

Tender Joint Count ◽

Control Group ◽

Tender Joint ◽

Composite Indices ◽

Number Of Patients ◽

Target Activity

Background:Disease modifying anti-rheumatic drugs (DMARD) can provide an unbalanced effect on individual components of the inflammatory process, which in some cases leads to an insufficiently correct assessment of the patient’s status when using composite activity indices [1].Objectives:To compare the results of the rituximab (RTX) efficacy assessment in patients with rheumatoid arthritis (RA) using different composite indices of disease activity.Methods:Patients with active RA observed in 23 medical centers of the Russian Federation were included. They were randomized into 2 groups in a 2:1 ratio. In the main group methotrexate (MTX) was prescribed at 15 mg per week and RTX infusions 600 mg on days 1 and 15. Patients in the control group received MTX 15 mg per week and placebo on days 1 and 15. If after 15 weeks 20% reduction of tender joint count (TJC) and swollen joint count (SJC) was not achieved, another DMARD was prescribed.Results:159 RA patients (131 women and 18 men) were included. The mean age of patients was 51.4±11.8 years, the median duration of RA – 2.8 [0.6; 5.8] years. At baseline DAS28, SDAI and CDAI in all cases assessed disease activity as high. 6 months after RTX administration DAS28 showed remission in 9%, low, moderate and high activity activity in 7%, 47% and 37% of cases, SDAI – in 7%, 12%, 34% and 47%, CDAI – in 7%, 11%, 30% and 52%, respectively. In the control group remission, low, moderate and high activity by DAS28 were revealed in 2%, 2%, 38% and 58%, by SDAI – in 2%, 4%, 35%, 59%, by CDAI – in 2%, 6%, 29%, 63% of patients respectively. After 6 months, in patients achieved the treatment target (remission or low activity) according to DAS28, SJC in 12 cases was 0, in 3 – 1 and in 1 – 2. TJC was 0 in 9 cases and in 7 patients ranged from 1 to 14. The level of C-reactive protein (CRP) in 14 cases was within the normal range and in 2 – increased. Erythrocyte sedimentation rate (ESR) was normal in all cases. SDAI after 6 months showed the target activity in 18 patients treated with RTX. In 12 of them the SJC was 0, in 4 – 1 and in 2 – 2. In 9 cases TJC was 0, in the rest patients it varied from 2 to 5. The level of CRP was normal in 15 patients, ESR – in all patients. CDAI met the target activity in 17 patients. In 12 of them, SJC was 0, in 3 – 1, in 2 – 2. The level of CRP was normal in 14, ESR – in all patients.Conclusion:Assessment of RTX efficacy with DAS28, SDAI, and CDAI in RA provided comparable number of patients who achieved remission or low disease activity 6 months after administration of the drug. The groups of patients who reached this target level of activity by DAS28, SDAI, and CDAI did not have significant differences in the values of main measures characterizing residual inflammatory activity, including SJC, TJC, ESR, and CRP.References:[1]Bastida C, Soy D, Ruiz-Esquide V, Sanmartí R, et al. Br J Clin Pharmacol. 2019 Aug;85(8):1710-1718.Disclosure of Interests:None declared

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AB0207 CLINICAL IMPACT OF ANTI-CARP ANTIBODIES IN RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4110 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1403.1-1404

Author(s):

M. Markovic ◽

B. Glisic ◽

M. Petronijevic

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Functional Status ◽

Joint Damage ◽

Control Group ◽

Antibody Concentration ◽

Open Label ◽

Positive Correlation ◽

Number Of Patients ◽

Peptide Antibodies

Background:Antibodies directed against carbamylated proteins (anti-CarP) have been recently introduced for the first time as a new biomarker in rheumatoid arthritis (RA) (1). Their presence is predictive for the development of RA (2). Anti-CarP antibodies are associated with the development of more severe forms of the disease in overall and anti-citrullinated peptide antibodies negative population of patients with RA (3). In the literature is still current the research which associate these antibodies with disease activity and functional status of patients.Objectives:This study investigated the incidence of anti-CarP positive findings in patients with RA on synthetic and biologic disease-modifying therapy (DMT) and the relationship between anti-CarP antibody status and both disability and disease activity.Methods:It was an open-label, observational, cross-sectional study. The trial included 70 patients with RA diagnosed on the basis of ACR 1987 and ACR / EULAR 2010 criteria, on treatment with synthetic and biological DMT, who attended the Clinic of Rheumatology, Military Medical Academy, from September to December 2018.The control group consisted of 18 healthy individuals. After approval of the institutional Ethical Committee and after patients have signed Informed Consent,the study was conducted. Disease activity score (DAS28) was determined for the assessment of RA activity, and the assessment of patients’ functional ability was performed using the Health assessment questionnaire disability index (HAQ-DI). Concentration of anti-CarP antibodies was determined by commercial ELISA anti-CarP quantitative sandwich immunoassay. The methods of descriptive and analytical statistics were used in statistical data processing.Results:Based on the cut-off value (5.9 ng / ml), no one in the control group had positive anti-CarP antibodies, while 34.7% of the subjects with RA were positive. The positive correlation was found between anti-CarP antibody concentration and DAS28 in all RA patients (p = 0.0003; Pearson r = 0.4829). The positive correlation was also found between anti-CarP antibody concentration and HAQ-DI in all RA patients (p = 0.0003; Pearson r = 0.4253).Conclusion:Anti-CarP antibodies were present in a significant number of patients with RA. This study demonstrated that patients with RA with higher concentrations of anti-CarP antibodies have higher disease activity and impaired functional status. It is undisputed that further and larger studies are needed to better determine the clinical significance of these antibodies.References:[1]Shi J, Knevel R et al. Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc Natl AcadSci U S A. 2011 Oct 18;108(42):17372-7.[2]Yee A, Webb T et al. Anti-CarP antibodies as promising marker to measure joint damage and disease activity in patients with rheumatoid arthritis. Immunol Res. 2015 Feb;61(1-2):24-30.[3]Brink M, Verheul MK et al. Anti-carbamylated protein antibodies in thepresymptomatic phase of rheumatoid arthritis, their relationship with multiple anticitrulline peptide antibodies and association with radiological damage. Arthritis Res Ther. 2015 Feb 7;17:25.Graphs 1 and 2.Correlation of anti-CarP antibody concentration with DAS28 and HAQ-DI in all RA patientsDisclosure of Interests:None declared

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POS0451 SERUM FETUIN-A AND VISFATIN LEVELS IN WOMEN WITH RHEUMATOID ARTHRITIS DEPENDING ON DISEASE ACTIVITY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1244 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 455.2-456

Author(s):

Y. Akhverdyan ◽

В. Zavodovsky ◽

E. Papichev ◽

J. Polyakova ◽

L. Seewordova

Keyword(s):

Rheumatoid Arthritis ◽

Blood Serum ◽

Disease Activity ◽

Transforming Growth Factor ◽

Average Level ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Healthy Individuals ◽

Fetuin A ◽

Grade Ii

Background:In recent years, the systemic effects of a number of cytokines have been actively studied, in particular, fetuin-A is considered a negative protein of the acute phase response, and visfatin, on the contrary, affects the activation of the cytokine cascade and has a pro-inflammatory effect. Taking into account that women suffer from rheumatoid arthritis (RA) more often, we investigated the levels of fetuin-A and visfatin in the blood serum of females in comparison with a group of healthy individuals and depending on the activity of the disease.Objectives:to study the levels of fetuin-A and visfatin in the blood serum of women suffering from RA, depending on the activity of the diseaseMethods:The study included 110 women with RA and 30 apparently healthy individuals. The inclusion criteria were: a diagnosis of RA verified based on the criteria of the American College of Rheumatology/European Anti-Rheumatic League (ACR/EULAR) 2010. The patients’ age ranged from 18 to 90 years. The control group included 30 conventionally healthy individuals. Serum fetuin-A and visfatin levels were determined by indirect enzyme-linked immunosorbent assay using commercial kits. RA activity was determined by the DAS28-CRP index. Activity 0-I was in 33 (30%) patients, grade II in 67 (60.9%), grade III in 10 (9.09%) patients.Results:The normal level of fetuin-A was calculated using the formula M±2σ in the group of conventionally healthy individuals and ranged from 653.55 to 972.19 μg/ml. In patients with grade 0-I RA activity according to DAS28, the mean serum fetuin-A level was 843.92±130.73 μg/ml, in patients with grade II activity - 742.37±98.85 μg / ml, with III the degree of activity - 663.9±123.7 μg/ml (p<0.001).The average level of visfatin in the blood serum in healthy individuals was 2.43±0.17 ng/ml. The level of normal values of visfatin in healthy individuals, defined as M±2σ, ranged from 0 to 5.07 ng/ml. The average level of visfatin in patients with RA was 6.27±0.18 ng/ml, which is significantly higher than in healthy individuals (p<0.001).In patients with 0-I degree of RA activity according to DAS28, the average level of visfatin in blood serum was 4.94±0.02 ng/ml, in patients with degree II activity - 5.08±0.02 ng/ml, with III degree of activity - 6.82±0.23 ng/ml (p<0.001).Conclusion:Thus, the level of fetuin-A in the blood serum of patients with RA is significantly lower in the case of a high degree of disease activity. The level of visfatin in the blood serum in women with RA is significantly higher in patients with a higher degree of disease activity. Therefore, the concentration values of fetuin-A and visfatin in the blood serum of patients with RA can be used in an integrated assessment of the prognosis of disease activity.References:[1]Inoue K, Ikeda Y, Yamanaka S, et al. Serum fetuinA levels in patients with rheumatoid arthritis [abstract]. Atherosclerosis. 2002;9(Suppl 1):233. doi: 10-1016/s1567-5688(08)70930-9[2]Janssens K, ten Dijke P, Janssens S, et al. Transforming growth factor-beta1 to the bone. Endocrine Reviews. 2005;26(6):743-74. doi:10.1210/er.2004-0001[3]Polyakova J, Korolik O, Papichev E, et al. The role of «new» cytokines in the pathogenesis rheumatoid arthritis. Ann Rheum Dis. 2018; 78(2): 1497Disclosure of Interests:None declared

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Sustained Clinical Remission and Rate of Relapse After Tocilizumab Withdrawal in Patients with Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.121427 ◽

2013 ◽

Vol 40 (7) ◽

pp. 1069-1073 ◽

Cited By ~ 31

Author(s):

Luis Aguilar-Lozano ◽

Jose Dionisio Castillo-Ortiz ◽

Cesar Vargas-Serafin ◽

Jorge Morales-Torres ◽

Adriana Sanchez-Ortiz ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Clinical Remission ◽

Disease Activity Score ◽

Additional Data ◽

Clinical Relapse ◽

Antiinflammatory Drugs ◽

Open Label ◽

Low Disease Activity ◽

Number Of Patients

Objective.Data on when to stop use of biological agents in rheumatoid arthritis (RA) are scant. We assessed the length of remission and the rate of clinical relapse in patients with RA who had to discontinue treatment with tocilizumab (TCZ) because of the ending of longterm (5 yrs) open-label clinical trials.Methods.All patients at 2 participating centers in Mexico were in remission, defined as Disease Activity Score 28 ≤ 2.6, with no swollen joints at the time of the last TCZ infusion. Patients were followed thereafter every 8 weeks for 12 months or until relapse. Relapse was defined as the presence of ≥ 1 swollen joint. Doses of methotrexate and antiinflammatory drugs were not changed during the followup period.Results.Forty-five patients were analyzed, 87% were women (mean age 52 yrs, mean disease duration 14 yrs). During the 12 months of followup, 44% of patients maintained remission. Relapses occurred in 56% of patients: 14 during the first 3 months after the last TCZ administration. Retreatment using other agents achieved low disease activity or remission.Conclusion.Longterm clinical remission is possible in a number of patients with RA after suspension of TCZ. This effect has also been reported with other biologic agents. Additional data are required to support recommendations for discontinuing a biological agent after achieving remission.

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

Life ◽

10.3390/life11121385 ◽

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.

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Thiol/Disulfide homeostasis in patients with rheumatoid arthritis

Romanian Journal of Internal Medicine ◽

10.2478/rjim-2018-0025 ◽

2019 ◽

Vol 57 (1) ◽

pp. 30-36 ◽

Cited By ~ 1

Author(s):

Ayca Tuzcu ◽

Rabia Aydogan Baykara ◽

Ahmet Omma ◽

Gunseli Karaca Acet ◽

Erdal Dogan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Oxidative Stress ◽

Disease Activity ◽

Negative Correlation ◽

Disease Activity Score ◽

Thiol Group ◽

Activity Score ◽

Control Group ◽

Healthy Individuals ◽

Healthy Female

Abstract Background. Oxidative stress may play an important role in rheumatoid arthritis (RA) etiopathogenesis. The thiol group is a very strong antioxidant. In this study, we aimed to investigate the presence of oxidative stress in patients with RA by evaluating thiol/disulfide homeostasis. Material and methods. A total of 50 female RA patients and 50 healthy female controls were included in this study. Thiol and disulfide values were calculated utilizing novel methods. Results. Native thiol (p < 0.001) and total thiol (p < 0.001) levels of RA patients were significantly lower compared to values in the control group. However, the disulfide (p < 0.001) levels of RA patients were strongly higher than in healthy individuals. A negative correlation was found between thiol and disease activity score-28 among the patients, whereas a positive correlation was found between disulfide and disease activity score-28 among the patients. Conclusion. We found that the thiol–disulfide rate deteriorated in RA patients, with the proportion of disulfide increasing. There is a strong correlation between the decrease in thiol levels, increase in disulfide levels and the disease activity scores.

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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

Modern Rheumatology Journal ◽

10.14412/1996-7012-2021-3-20-26 ◽

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.

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P–450 Effects of rheumatoid arthritis and methotrexate therapy on ovarian reserve in infertile women

Human Reproduction ◽

10.1093/humrep/deab130.449 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

G Vlasova ◽

S Perminova

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Ovarian Reserve ◽

Small Sample Size ◽

Genetic Material ◽

Main Group ◽

Small Sample ◽

Control Group ◽

Proliferating Cells ◽

Number Of Patients

Abstract Study question Do patients with infertility and rheumatoid arthritis (RA) treated with methotrexate (MTX) have ovarian reserve alterations? Summary answer Women with infertility and RA treated with MTX were found to have statistically significant decrease of ovarian reserve. What is known already Rheumatoid arthritis (RA) is one of the most prominent inflammatory diseases affecting women of child-bearing age [Brouwer J. et al, 2014]. RA and its treatment may interfere with the female reproductive physiology. The vast majority of patients with RA are treated with methotrexate (MTX) which is a folate antagonist that inhibits DNA synthesis. MTX, which is the anchor drug in RA, targets actively proliferating cells including the oocytes and granulosa cells which may impair the ovarian reserve [Min Tun Kyaw et al, 2020]. Study design, size, duration A prospective case-control study that enrolled 72 female patients with infertility was conducted in the 2-year time period of September 2018 to October 2020. Participants/materials, setting, methods The main group comprised 32 patients with infertility and RA; the control group consisted of 40 women with infertility only. Patients with RA were stratified into subgroups based on whether or not they received MTX. To investigate ovarian reserve measurement of serum anti-Müllerian hormone (AMH) was used. The level of AMH was evaluated concerning RA duration and activity, as well as the age at initiation of MTX therapy, dosage, and treatment duration. Main results and the role of chance The mean age of the study population was 36±3 years. The duration of RA was 4 [3; 11] years. The low disease activity based on DAS28-ESR (disease activity score based on 28 joints using the erythrocyte sedimentation rate) prevailed(56.2%). In the main group 19(59.4%) women received MTX therapy. The MTX dosage was 15 [15;20]mg /wk, the duration of MTX therapy by the day of inclusion in the study was 18.7[1; 15]months. The AMH level was significantly lower in the main group (2.1 n /ml vs 2.73ng /ml, p = 0.043). The number of patients with decreased ovarian reserve (AMH level<1.0ng/ml) significantly prevailed in the group of patients with RA (25% vs 5%, p = 0.015). When assessing the AMH level in patients with RA who received MTX (n = 19) and patients in the control group, there was a tendency towards a decrease in the indicator in the first subgroup, but no statistically difference was found (p = 0.074). Correlation analysis of the dependence of AMH level on the patient age showed the most significant decrease in AMH in the patients with RA receiving MTX compared to the patients with RA who did not, and compared to all patients with RA regardless of the therapy received (rs=–0.563)(p < 0.05). Limitations, reasons for caution The lack of statistically significant data in certain cases may be due to the small sample size. Wider implications of the findings: RA and MTX administration are associated with a significant decrease in AMH levels. The age of initiation of the therapy is negatively correlated with the AMH level. In this regard, patients with already compromised reproductive function who are planning to receive MTX should be advised to preserve the genetic material. Trial registration number 567890

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