Rheumatoid Arthritis Rheumatoid Factor Research Articles

P106 Do high rheumatoid factor titres impact response to tumour necrosis factor inhibitors? Comparison of certolizumab pegol and adalimumab in patients with rheumatoid arthritis and high titres of rheumatoid factor: a post hoc analysis of a phase 4 trial.

Abstract Background/Aims In patients with rheumatoid arthritis (RA), high rheumatoid factor (RF) titres are considered a poor prognostic factor and are associated with higher disease activity, risk of radiographic progression and decreased response to TNF inhibitors (TNFis). Recent data suggests that patients with RA and high RF titre may achieve and maintain greater clinical improvement with TNFis without a crystallisable fragment (Fc) compared to TNFis with an Fc. In this analysis of the EXXELERATE trial, we assessed efficacy outcomes of certolizumab pegol (CZP), a PEGylated Fc-free TNFi, versus adalimumab (ADA; Fc-containing TNFi) in patients with RA and high RF titres. Methods The phase 4 EXXELERATE trial (NCT01500278) compared the efficacy and safety of CZP to ADA. Patients were randomised 1:1 to CZP 200 mg every two weeks (Q2W) plus methotrexate (MTX) or ADA 40 mg Q2W plus MTX. At Week 12 (Wk), patients were classified as responders or non-responders; non-responders were switched to the other TNFi with possible follow-up to Wk104. Here, we report drug plasma concentrations, mean disease activity score (DAS)28-CRP score and proportion of patients achieving low disease activity (LDA; threshold: DAS28-CRP ≤2.7) to Wk104. Results are stratified by RF titre quartile (≤Q3: ≤203 IU/mL; >Q3: >203 IU/mL; measured by Roche Tina-quant®) and reported as observed data. Results Baseline data by RF quartile were available for 453 CZP-randomised patients (≤Q3: n = 334; >Q3: n = 119) and 454 ADA-randomised patients (≤Q3: n = 347; >Q3 n = 107). Baseline characteristics were similar between CZP- and ADA-randomised patients across the RF titre quartiles. At Wk12, 66 CZP-treated patients switched to ADA and 59 ADA-treated patients switched to CZP. At Wk104, mean ADA concentrations were 22.9% lower in patients with RF >Q3 (mean [SD] 4.8 [3.0]) vs those with RF ≤Q3 (6.2 [4.0]); in CZP-treated patients, this difference was smaller (13.0%) in patients with RF >Q3 (23.3 [15.4]) vs those with RF ≤Q3 (26.7 [13.1]). For patients in RF ≤Q3, mean DAS28-CRP scores were similar between CZP- and ADA-treated patients through Wks0-104 (mean [SD] DAS28 at Wk104: 2.48 [1.18] CZP vs 2.49 [1.14] ADA). However, for patients in RF >Q3, mean [SD] DAS28-CRP scores were nominally lower in CZP- vs ADA-treated patients (Wk104: 2.50 [1.18] CZP vs 2.93 [1.22] ADA). A similar pattern was observed for the proportion of patients achieving LDA at Wk104 (≤Q3: 64.8% CZP vs 65.1% ADA; >Q3: 65.7% CZP vs 48.3% ADA). Conclusion CZP-treated patients with RA and high titre RF had similar drug concentrations and clinical responses to patients with RA and low titre RF, a pattern not observed in ADA-treated patients. These data, together with previous reports where CZP showed consistent efficacy irrespective of baseline RF titre, suggest CZP may be a suitable therapy for patients with RA and high RF titre. Disclosure J.S. Smolen: Honoraria; AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung, Sanofi, and UCB Pharma. Grants/research support; AbbVie, AstraZeneca, Eli Lilly, Novartis and Roche. Other; Editor of Annals of the Rheumatic Diseases, Co-editor of Rheumatology 7E/8E, Convenor of EULAR Task Forces and T2T Task Forces. P.C. Taylor: Consultancies; AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead, GSK, Janssen, Nordic Pharma, Pfizer, Sanofi and UCB Pharma. Grants/research support; Galapagos. Y. Tanaka: Honoraria; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Gilead, GSK, Pfizer, Taiho, Taisho. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Eisai, Eli Lilly, Gilead, GSK, Pfizer, Taiho and Taisho. Grants/research support; Chugai, Eisai, Mitsubishi-Tanabe, Taisho. C. Cara: Shareholder/stock ownership; UCB Pharma. Other; Employee of UCB Pharma. B. Lauwerys: Shareholder/stock ownership; UCB Pharma. Other; Employee of UCB Pharma. R. Xavier: Consultancies; AbbVie, AstraZeneca, Janssen, Organon, UCB Pharma. Member of speakers’ bureau; AbbVie, AstraZeneca, Janssen, Organon, and UCB Pharma. J.R. Curtis: Consultancies; AbbVie, Amgen, BMS, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche, UCB Pharma. Grants/research support; AbbVie, Amgen, BMS, Corrona, Crescendo, Genentech, Janssen, Pfizer, Roche, UCB Pharma. T.R. Mikuls: Consultancies; Horizon Therapeutics, Pfizer, Sanofi, UCB Pharma. Royalties; Elsevier, Wolters Kluwer Health (UpToDate). Grants/research support; Horizon Therapeutics. M. Weinblatt: Consultancies; AbbVie, Aclaris, Amgen, Aqtual, BMS, CorEvitas, Eli Lilly, GSK, Gilead, Horizon, Johnson and Johnson, Prometheus, Pfizer, Rani, Revolo, Sanofi, Scipher, Sci Rhom, Set Point, UCB Pharma. Grants/research support; AbbVie, Aqtual, BMS, Janssen.

Effects of Human Leukocyte Antigen DRB1 Genetic Polymorphism on Anti-Cyclic Citrullinated Peptide (ANTI-CCP) and Rheumatoid Factor (RF) Expression in Rheumatoid Arthritis (RA) Patients.

Rheumatoid arthritis (RA) is a systemic disease characterized by non-infectious inflammation of the joints and surrounding tissues, which can cause severe health problems, affect the patient's daily life, and even cause death. RA can be clinically diagnosed by the occurrence of blood serological markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP). However, about 20% of RA patients exhibit negative results for both markers, which makes RA diagnosis difficult and, therefore, may delay the effective treatment. Previous studies found some evidence that human leukocyte antigen (HLA)-related genes might be the susceptibility genes for RA and their polymorphisms might contribute to varieties of susceptibility and disease severity. This study aimed for the genetic polymorphisms of the RA patient genome and their effects on the RA patient's serological makers, RF and anti-CCP. A total of 4580 patients' electronic medical records from 1992 to 2020 were retrieved from the China Medical University Hospital database. The most representative single-nucleotide polymorphisms (SNPs) were identified through a genome-wide association study (GWAS) followed by enzyme-linked immunosorbent assay (ELISA) validation using the blood from 30 additional RA patients. The results showed significant changes at the position of chromosome 6 with rs9270481 being the most significant locus, which indicated the location of the HLA-DRB1 gene. Further, patients with the CC genotype at this locus were more likely to exhibit negative results for RF and anti-CCP than those with the TT genotype. The C allele was also more likely to be associated with negative results for RF and anti-CCP. The results demonstrated that a genetic polymorphism at rs9270481 affected the expression of RF and anti-CCP in RA patients, which might indicate the necessity to develop a personalized treatment plan for each individual patient based on the genetic profile.

Epicardial Fat Thickness: A Cardiometabolic Risk Marker in Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory disorder of unknown etiology which mainly involves synovial joints. However, the corresponding systemic inflammation may result in disorders of multiple other organ systems. Several organs and organ systems are potentially involved in RA, particularly in severe diseases. The organs most involved are the lung, heart, eyes, and nervous system. Extra-articular manifestations of RA may develop even before the onset of arthritis. Emerging epidemiological evidence shows that cardiovascular disease (CVD) accounts for near about 50% of RA-associated death. Epicardial fat thickness (EFT) has recently emerged as a new marker of cardiometabolic risk. Although Epicardial fat (EF) is needed for heart muscle function, given its intrinsic inflammatory status, EFT displays the potential to serve as a therapeutic target in patients with RA.Objectives: To evaluate EFT using echocardiography in RA patients compared to age and sex-matched control and to find the factors associated with EFT in RA patients.Materials and methods: This current study was conducted in the Department of Medicine, Postgraduate Institute of Medical Education & Research. The study was conducted from November 2016 to March 2018. Patients with BMI ≥ 30 kg/m2, diabetes mellitus, primary hyperlipidemia, and uncontrolled hypertension were particularly excluded. Thirty patients of age and sex-matched controls were also taken for the study. All the patients and controls selected for the study were subjected to detailed history taking and clinical examination. They were subjected to lab investigations and echocardiography. The 30 RA patients included in the study were diagnosed according to the 2010 ACR-EULAR criteria. Disease activity was measured by the disease activity score (DAS28) index.Results: Group 1 included 30 patients with RA and group 2 included 30 age and sex-matched controls. Pearson correlation analysis was done between EFT and other variables. Only HDL, erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hS-CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), DAS28, and disease duration were found to have a significant correlation with EFT.Conclusion: In patients with RA, EFT, left ventricular mass, and diastolic dysfunction are increased in RA patients compared to healthy controls. Out of the conventional CVD risk factors, only HDL was associated with increased EFT in RA patients. In RA patients, DAS28, disease duration, RF, anti-CCP, and markers of inflammation (ESR, hs-CRP) were also associated with increased EFT.

Correlation genotype-phenotype: MEFV gene mutations and Moroccan patients with rheumatoid arthritis.

Introductionrheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting the joints. Arthritic disorders are associated with mutations of the Mediterranean fever (MEFV) gene. The aim of this study is to show whether MEFV mutations will be involved in the pathogenesis of RA, to explore the frequency of these mutations and to study the genotype-phenotype correlation between mutations in this gene and a cohort of Moroccan patients with rheumatoid arthritis (RA).Methodsthe present study included 100 patients with RA and 200 control group (CG) who were unrelated individuals from the same ethnic. All patients were tested for auto-antibodies: cyclic citrullinated peptide (ACPA/anti-CCP2), rheumatoid factor (RF) and were analyzed by Sanger Sequencing of the 2 and 10 exons of MEFV gene (hot-spot according to the literature).Resultswe detected 13 missense variants already MEFV gene mutation reported in the literature (S154T, G222A, G230L, L611H, L695A, M694V, I720M, A737L, P758S, L709A, T732A, G687A and P743L). Carrier rates of MEFV gene mutations were 24/100 (24%) for the RA group and 4/200 (4%) for CG. In the RA group, we observed that no man has presented with MEFV mutation. In the RA group, while gender, BMI, RF and ACPA were significantly higher in the mutation carrier group than those of the non-carrier group (p<0.01). The level of C-reactive protein and HAQ were slightly elevated in the carrier group but not significant. No other significant differences were observed between patients with MEFV mutations and those without MEFV mutations.Conclusionthe results of this study suggest that MEFV gene mutations appear to be an aggravating factor severity of RA and consequently, patients with RA might be screened for MEFV gene mutations in countries where FMF is frequent. We report also that our study is the first one in our country Morocco.

OP0215 MENTAL HEALTH, SLEEP AND COGNITION CHARACTERISTICS IN RHEUMATOID ARTHRITIS AND ASSOCIATIONS WITH RHEUMATOID FACTOR STATUS IN THE UK BIOBANK

Background:There are significant gaps in the literature regarding sleep, mental health, and cognition for people with rheumatoid arthritis (RA) despite being important aspects of patients’ overall quality of life. Similarly, there is a lack of understanding about the role of rheumatoid factor (RF) on these domains.Objectives:The aim of the current study was to characterize mental health, cognition, and sleep variables in people with RA and to compare these associations in people with positive RF (RF+) and negative RF (RF-) in a large population cohort.Methods:This cross-sectional study used baseline data from the UK Biobank cohort (n= 502,506) to compare people with and without RA and people that are RF+ versus RF- on a variety of sociodemographic, lifestyle, illness-related factors and depression, neuroticism, performance on cognitive tests and sleep-related factors. Logistic regression analyses were also performed to determine whether RF seropositivity was associated with mental health, cognition, and sleep variables. We adjusted for the covariates of age, sex, ethnicity, deprivation index, smoking status, BMI and alcohol intake.Results:In this sample 5,907 people self-reported having RA (1.17%), of which 74% were RF- and 26% were RF+. There were significant differences (p &lt; 0.05) between people with and without RA for depression, neuroticism, nap during the day, getting up in the morning, insomnia, reaction time, fluid intelligence and prospective memory. There were significant differences (p &lt; 0.05) between RF+ and RF- people for depression, neuroticism, sleep duration, nap during the day, getting up in the morning, insomnia, and reaction time. In the unadjusted regression analyses neuroticism (B=-0.06, SE= 0.01, p &lt; 0.001), sleep duration (B=0.02, SE= 0.005, p &lt; 0.001), nap during the day (OR=1.28, 95% CI: 1.02-1.65, p &lt; 0.05) and reaction time (B=4.55, SE=0.53, p&lt; 0.001) were significantly associated with RF status. After adjusting for covariates, only sleep duration (B=0.01, SE=0.005, p&lt; 0.01) remained significant.Conclusion:The current study suggests that RA diagnosis and RF status are associated with differences in mental health, sleep, and cognition, highlighting the importance of addressing these aspects in clinical settings and future research.Disclosure of Interests:None declared

Body Mass Index and Disease Activity in Chronic Inflammatory Rheumatic Diseases: Results of the Cardiovascular in Rheumatology (Carma) Project.

Objective: Since obesity has been associated with a higher inflammatory burden and worse response to therapy in patients with chronic inflammatory rheumatic diseases (CIRD), we aimed to confirm the potential association between body mass index (BMI) and disease activity in a large series of patients with CIRDs included in the Spanish CARdiovascular in rheuMAtology (CARMA) registry. Methods: Baseline data analysis of patients included from the CARMA project, a 10-year prospective study of patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) attending outpatient rheumatology clinics from 67 Spanish hospitals. Obesity was defined when BMI (kg/m2) was >30 according to the WHO criteria. Scores used to evaluate disease activity were Disease Activity Score of 28 joints (DAS28) in RA, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in AS, and modified DAS for PsA. Results: Data from 2234 patients (775 RA, 738 AS, and 721 PsA) were assessed. The mean ± SD BMI at the baseline visit were: 26.9 ± 4.8 in RA, 27.4 ± 4.4 in AS, and 28.2 ± 4.7 in PsA. A positive association between BMI and disease activity in patients with RA (β = 0.029; 95%CI (0.01–0.05); p = 0.007) and PsA (β = 0.036; 95%CI (0.015–0.058); p = 0.001) but not in those with AS (β = 0.001; 95%CI (−0.03–0.03); p = 0.926) was found. Disease activity was associated with female sex and rheumatoid factor in RA and with Psoriasis Area Severity Index and enthesitis in PsA. Conclusions: BMI is associated with disease activity in RA and PsA, but not in AS. Given that obesity is a potentially modifiable factor, adequate control of body weight can improve the outcome of patients with CIRD and, therefore, weight control should be included in the management strategy of these patients.

Validity of endocan as a biomarker in systemic sclerosis: relation to pathogenesis and disease activity

BackgroundSystemic sclerosis (SSc), an autoimmune disease, has endothelial dysfunction and tissue fibrosis. The lack of its specific activity markers urges the research. Endocan is an immunomodulatory protein associated with endothelial dysfunction. We aimed to measure of the endocan level in systemic sclerosis (SSc) patients’ sera to test its relation to disease activity and treatment responses. Also, to evaluate its specificity by comparing these data with Behçet’s disease (BD) and rheumatoid arthritis (RA) patients’ data.ResultsSSc and RA patients were in activity but in the BD group; eight were active and seven were inactive. The endocan level was higher in the three groups in comparison to the controls without statistically significant differences (p value RA 0.697, SSc 0.063, and BD 0.196). A statistically significant difference in endocan levels between SSc patients with and without vascular manifestations (pulmonary hypertension and finger pitting ulcers, p < 0.0001, p = 0.0097, respectively). There were no significant correlations between endocan level and the erythrocyte sedimentation rate and C-reactive protein (positive rheumatoid factor for RA) in the three groups (p > 0.05). There were no significant correlations between endocan level and activity scores in the three groups (p > 0.05). The cut-off value of endocan was 1.3 ng/ml.ConclusionEndocan is a non-specific marker for the vascular pathogenesis in systemic sclerosis but not a good predictor for its activity.

Major vault protein/lung resistance related protein: a novel biomarker for rheumatoid arthritis.

Rheumatoid arthritis (RA) can lead to joint destruction and early institution of effective treatment can preserve joint function. Biomarkers can establish early diagnosis and predict effect of treatment. Vault particles, large cytoplasmic ribonucleoprotein particles that participate in inflammation, might serve as biomarkers. The aim of this study was to assess the diagnostic and the prognostic value of major vault protein (MVP) and their antibodies in RA. Serum samples from 159 RA patients, 26 early RA (ERA) patients, 21 patients with osteoarthritis (OA) and 30 healthy individuals were tested for MVP, anti-cyclic citrullinated peptide (anti-CCP) and C-reactive protein (CRP) using enzyme-linked immunosorbent assays (ELISA). Rheumatoid factor (RF) was tested by nephelometry, and anti-MVP antibodies were detected by anti-MVP peptide ELISA using an in-house protocol. MVP levels were higher in RA and ERA, compared to OA and healthy controls (p<0.00001). A combination of MVP with RF or anti-CCP showed an improved diagnostic accuracy compared to RF or anti-CCP alone in RA and ERA. MVP exhibited similar AUC levels to anti-CCP and RF in RA whereas in ERA, MVP exhibited the same or slightly higher AUC levels, compared to anti-CCP and RF, respectively. High MVP levels were associated with lack of response to treatment. Levels of anti-MVP peptide 2 antibodies were significantly higher in RA compared to healthy controls (t= 2.73, p=0.007). MVP and autoantibodies against MVP may have the potential to serve as diagnostic and prognostic biomarkers in RA.

Selective Increment of Synovial Soluble TYRO3 Correlates with Disease Severity and Joint Inflammation in Patients with Rheumatoid Arthritis.

Objective To investigate the role of TAM receptors in rheumatoid arthritis (RA) by determining synovial tissue TAM receptor expression, synovial fluid levels of soluble TAM receptors, and the relationship between soluble TAM receptors, joint inflammation and disease activity. Methods TAM receptor expression was determined by immunohistochemistry on the synovium from RA and osteoarthritis (OA) patients. Soluble (s) Tyro3, sAxl, sMer, and their ligand Gas6 were measured by ELISA in the synovial fluid of RA (n = 28) and OA (n = 12) patients and cytokine levels by multiplex immunoassay in RA samples. Correlation analyses were performed among sTAM receptors with local cytokine levels; systemic disease parameters like erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), and anticyclic citrullinated peptide antibodies (ACPA); and disease activity scores (DAS28-ESR) in RA patients. Results TAM receptors were expressed on different locations in the synovial tissue (lining, sublining, and blood vessels), and a similar expression pattern was observed in RA and OA patients. Synovial fluid sTyro3 and sMer were significantly enhanced in RA compared to OA patients, whereas no significant differences in sAxl and Gas6 levels were found. In RA samples, sTyro3 levels, but not sMer, correlated positively with proinflammatory local cytokines and the systemic factor erythrocyte sedimentation rate. Moreover, stratification analysis showed high sTyro3 levels positively correlated with higher DAS28-ESR and in RF and ACPA double positive RA patients. Conclusion sTyro3 in the synovial fluid of RA patients correlates with local inflammatory molecules and systemic disease activity. These findings suggest that the reduced negative control of cell activation by TAM receptors due to their shedding in the synovial fluid, mainly sTyro3, favoring joint inflammation in RA patients.

A predominant involvement of the triple seropositive patients and others with rheumatoid factor in the association of smoking with rheumatoid arthritis

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anti-citrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10–8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10–16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+1+2vs. RF−0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms.

Диагностическое значение анти-Sa антител и антител к гетерогенному нуклеарному рибонуклеопротеину К при ревматоидном артрите

Annotation The aim of the research is to determine the levels and frequency of antibodies popularity to cyclic citrullinated peptide (APCCP), rheumatoid factor (RF), anti-Sa antibodies and antibodies to heterogeneous nuclear ribonucleoprotein K (anti-gRNP K) in rheumatoid arthritis (RA) and to compare their diagnostic characteristics, and also to determine sensitivity and specificity of anti-Sa antibodies, anti-hRNP K in seronegative RA. Material and methods. The study included 270 patients with RA and 50 healthy individuals. The levels of ACCP, anti-Sa, anti-hRNP K were assessed in blood serum samples from patients by enzyme-linked immunosorbent assay using commercial test systems. RF levels were assessed by kinetic nephelometry on automatic analyzer. Results. The levels and popularity frequency of the studied antibodies in patients with RА were significantly higher than in healthy individuals (p &lt;0.05). Tests based on ADCP detection had the highest indices of sensitivity and specificity for RA diagnosis; sensitivity - 78.01%, specificity - 100.00%, and RF - 70.64%, specificity 96.97%. In case of serogegative APCCP and RA RF, diagnostic sensitivity of anti-Sa antibodies determination was 50.00%, specificity was 96.77%, sensitivity of anti-hRNP K antibodies determination was 55.56%, and specificity was 100.00%. Conclusion. Considering high specificity of tests for anti-Sa and anti-hRNP K antibodies in seronegative RA, they can be considered as additional confirmatory diagnostic tests.

Time course of changes in the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with rheumatoid arthritis during therapy with an interleukin-6 receptor inhibitor

Objective : to investigate the impact of therapy with the interleukin-6 receptor inhibitor tocilizumab (TCZ) on the time course of changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in patients with rheumatoid arthritis (RA) during a 12-month follow-up period. Subjects and methods . 31 RA patients (26 women and 5 men) with an inadequate response and/or intolerance to disease-modifying antirheumatic drugs (DMARDs) were included. Their median age was 54 [45; 61] years; the disease duration – 110 [62; 168] months; DAS28 – 6.2 [5.1; 7.1]; SDAI – 35.0 [23.9; 51.0], and CDAI – 30.0 [21.0; 42.0]. All the patients were seropositive for rheumatoid factor (RF), 84% – for anti-cyclic citrulinated peptide (anti-CCP) antibodies. Extra-articular manifestations were found in 54% of patients. Patients with chronic heart failure were not included. The RA patients were found to have a high frequency of traditional risk factors for cardiovascular diseases (CVD): hypertension (75%), dyslipidemia (61%), smoking (17%), overweight (61%), a family history of CVD (36%) , and hypodynamia (68%). Coronary heart disease was diagnosed in 11% of patients. The inefficacy of three or more NSAIDs was noted in 45% of cases; intolerance to previous therapy with NSAIDs was observed in 55%. The patients received TCZ at a dose of 8 mg/kg every 4 weeks: 39% received TCZ alone; 61% – in combination with methotrexate (MTX), the MTX median dose was 20 [18; 25] mg/week. The level of NT-proBNP was measured before and 12 months after TCZ therapy. Results and discussion . After 12 months of treatment with TCZ 54% of patients had disease remission (DAS28 <2.6), 46% – low disease activity (DAS28 <3.2). Median DAS28 value decreased from 6.2 [5.1; 7.1] to 2.7 [1.5; 3.3] (p<0.01), erythrocyte sedimentation rate (ESR) – from 38 [24; 54] to 8 [4; 16] mm/h (p<0.01), C-reactive protein (CRP) – from 27 [10; 49] to 0.5 [0.2; 0.7] mg/L (p<0.01) and NT-proBNP – from 75.8 [43.0; 100.7] to 37.8 [25.1; 78.5] pg/l (p=0.01), although the frequency of its increased values (≥100 pg/ml) remained unchanged (13%). There was a correlation of ΔNT-proBNP with ΔESR (r=0.43; p<0.05) and with ΔCRP (r=0.46; p<0.05). No association was found between ΔNT-proBNP, RA activity measures, RF, and anti-CCP. The level of NT-proBNP in patients treated with TCZ alone and in combination with MTX did not differ considerably. Conclusion . After 12 months of treatment to suppress RA activity, there was a decrease in NT-proBNP levels when TCZ was used alone and in combination with MTX. The lower concentration of NT-proBNP was associated with a reduction in acute phase measures (CRP and ESR). Control of RA activity results in the reduced damaging effect of inflammation on the myocardium.

Effects of Genetic Polymorphisms of Programmed Cell Death-1 in Susceptibility with Rheumatoid Arthritis in Najaf Population

Background: The prevalence of Rheumatoid Arthritis (RA) has been raised in Iraq. The medical costs of such increased prevalence are high. Global studies have revealed polymorphisms of PD1 (Program Death 1) gene to be associated with Rheumatoid Arthritis (RA). This polymorphism can cause changes in various metabolic variables. Methods: The current study consists of 100 RA patients and 100 healthy control individuals. Variable parameters data included Anti-Cyclic cytrulinated peptide expression (ACCP), Rheumatoid factor (RF), C-Reactive Protein (CRP) in serum and Erythrocytes sedimentation rate (ESR) leveles. Genotyping of PD1gene polymorphism is carried out by RFLP-PCR. Various statistical analyses were applied to analyze the data.&#x0D; Results: The estimation of immunological and biochemical data pointed out significant differences in Gender, RF, ACCP, CRP, ESR and age in RA when compared with those of the control group. The genotyping results were found to be consistent with Hardy-Weinberg equilibrium. The analysis of the genotype distribution under various inheritance models highlighted significant differences in SNP of PD1 gene polymorphism among RA patients when compared with the control group under the dominant homozygote, heterozygote and recessive homozygote. The genotype and allele frequencies of the PD1 SNP rs11568821; genotype GA was significantly increased in RA compared with controls (45% and 24%, respectively) (P=0.0020),(OR =2.5909),(95% CI 1.4-4.7) . Subjects who carried A allele were significantly more likely to develop RA three folds AA(OR=3.3529, 95% CI=1.1691-9.6160, P=0.0244). Clinical characteristics were observed to change significantly with respect to the genotype distribution of the investigated SNP. Conclusion: PD1 gene polymorphisms (rs11568821) is implicated in the pathogenesis of Rheumatoid arthritis in Najaf population.

Clinical Utility of Rheumatoid Factor and Anti-Cyclic Citrullinated Peptide Antibody in the Diagnosis and Evaluation of Disease Activity in Patients of Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA), a chronic systemic inflammatory disease affects around 0.75% of adult Indian population and is characterized by multiple deformities. Diagnosis of RA is primarily based on clinical manifestations and serological evidence, with rheumatoid factor (RF) being the serological marker tested the most. The diagnostic specificity of RF in RA is poor as it is found in other rheumatic and non-rheumatic diseases. Anticyclic citrullinated peptide antibodies (Anti-CCP) are a better diagnostic and prognostic marker for RA, in contrast to RF, because of their early presence and high specificity. Methods: The present study was conducted in the Department of Microbiology and Department of Rheumatology Government Medical College and Hospital Srinagar from January 2017 to December 2017 where in a total of 300 patients with clinical features suggestive of RA were included. Anti-CCP antibody, RF, and C-Reactive Protein (CRP) levels were estimated in all these patients. Results: On the basis of clinical evaluation and serological evidence, 216 (72%) patients were diagnosed as cases of RA and 84 (28%) were classified as having other non-rheumatoid disorder Females represented majority of the patients. Anti-CCP antibody, RF and CRP reactivity were significantly more in RA patients. The sensitivity and specificity of anti-CCP antibody and RF were found to be 60.65% & 96.43% and 49.07% & 76.19% respectively. Conclusions: Anti-CCP antibodies are a highly specific marker for RA in our patient population making it a good modality in patients with early disease, in whom a timely diagnosis is most needed. The low sensitivity of the test indicates that a negative anti-CCP antibody test does not exclude disease, but its high specificity means that a positive result markedly increases the probability that the patient will have RA. Thus, anti-CCP testing is a must in patients suspected of having RA to aid in early diagnosis.

YKL-40 Levels in Rheumatoid Arthritis and Their Correlation with Disease Activity: A Meta-analysis

Objective. To examine the relationship of serum/plasma YKL-40 levels with rheumatoid arthritis (RA) and their correlation with RA activity and rheumatoid factor (RF) level. Methods. We performed a meta-analysis comparing the serum/plasma YKL-40 lev-els between patients with RA and controls and examined the correlation coefficients of the circulating YKL-40 level with the RF level and RA activity based on the 28-joint disease activity score (DAS28), erythrocyte sedimentation rate (ESR), and C-re-active protein (CRP) level. Results. Nine studies (707 patients with RA and 1,041 controls) were included in the meta-analysis. The YKL-40 levels were significantly higher in the RA group than in the control group (standardized mean difference [SMD]=1.071, 95% confidence interval [CI]=0.726∼1.417, p＜0.001). Stratification by ethnicity showed significantly ele-vated YKL-40 levels in the RA groups from European, Asian, North American, and Arab populations. The YKL-40 level was sig-nificantly higher in the RA group than in the control group in both age- and sex-matched and only age-matched populations (SMD=0.937, 95% CI=0.554∼1.320, p＜0.001; SMD=2.951, 95% CI=1.389∼4.512, p＜0.001, respectively). Subgroup analysis by sample size showed significantly increased YKL-40 levels in the RA group in both small (n＜100) and large (n＞100) populations. Meta-analysis of correlation coefficients showed a significant positive correlation between the YKL-40 levels and DAS28, ESR, CRP level, and RF level (DAS28: correlation coefficient=0.381, 95% CI=0.044∼0.640, p=0.028; RF level: cor-relation coefficient=0.341, 95% CI=0.176∼0.487, p＜0.001). Conclusion. The circulating YKL-40 levels are high in patients with RA and positively correlate with RA activity and RF level. (J Rheum Dis 2019;26:257-263)

Autoantibody and metalloproteinase activity in early arthritis

ObjectivesThe aim of the study was to evaluate the frequency of anti-mutated citrullinated vimentin antibodies (a-Sa), anti-citrullinated α-enolase peptide 1 antibodies (a-CEP-1), anti-filaggrin antibodies (AFAs), heterogeneous nuclear ribonucleoprotein compies/anti-RA33-antibodies (a-hnRNP/RA33), anti-carbamylated protein antibodies (a-CarP), and metalloproteinase (MMPs) activity in patients with early inflammatory arthritis (EIA).MethodsSeventy-four patients with EIA: 51 diagnosed with RA (rheumatoid arthritis) and 23 with UA (undifferentiated arthritis), and 20 healthy volunteers were enrolled to the study. Inflammatory markers, rheumatoid factor (RF), and antibodies mentioned above were assessed in all patients.ResultsIn the EIA group, we observed significantly higher concentration of a-CEP-1 (65.8 ± 111.6 RU/mL) than in controls (2.0 ± 0.0 RU/mL). In RF(+) RA patients, we observed higher concentration of a-Sa and a-CEP-1 than in other groups. A-Sa were positive in 69% of RF(+) RA, 37% of RF(−) RA, 26% of UA patients and in 10% of controls. A–CEP-1 were positive in 77% of RF(+) RA patients, in 56% of RF(−) RA patients, in 8.7% of UA patients, but they were negative in controls. In patients with RF(+) RA, positive a-CarP were present statistically significantly more often than in RF (−) RA patients. No statistically significant difference in frequency of a-hnRNP/RA33 and AFA between RF(+) RA, RF(−) RA, and UA was observed.ConclusionsOur results suggest that a-CEP-1 may help in differentiation between RF(−) RA and UA. a-CEP-1 and a-Sa may be useful while diagnosing EIA. a-CarP may be used in differentiation of RA RF(−) and UA. However, a follow-up study is needed to evaluate the prognostic value of analyzed antibodies.

Prevalence and predictive value of high-positive rheumatoid factor and anti-citrullinated protein antibody levels in nonarthritic patients with chronic hepatitis C infection.

In order to increase diagnostic sensitivity for early disease in rheumatoid arthritis (RA), new classification criteria were approved in 2010 by the American College of Rheumatology and the European League Against Rheumatism. One of the criteria, a high-positive rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) level, was given a high score of 3. However, the increased prevalence of RF in patients with chronic hepatitis C virus (HCV) infection markedly diminishes the diagnostic specificity of serum RF for RA in these patients. There are no published data on the prevalence and predictive value of high-positive RF and ACPA; thus, we investigated high-positive RF and ACPA levels in nonarthritic patients with chronic HCV infection. Anti-citrullinated protein antibody and total RF were determined in serum from nonarthritic patients with chronic HCV infection (all had HCV RNA viremia). In 271 HCV-infected patients, positive RF, positive ACPA, high-positive RF, and high-positive ACPA were detectable in 47.2%, 1.1%, 8.9% and 1.1%, respectively. In these patients, fatty liver was an independent factor for high-positive RF. In contrast to RF, ACPA is not increased in HCV infection. High-positive RF is not unusually present in nonarthritic patients with chronic HCV infection. ACPA may have improved value for the diagnosis of RA in this patient population. In patients with HCV infection, fatty liver may be a risk factor for high-positive RF.

A Retrospective Study: The Significance of Combined Testing of Serum Markers for Diagnosis of Rheumatoid Arthritis.

BackgroundThere have been few studies on the value of various antibody combinations in rheumatoid arthritis (RA) diagnosis, and a lack of studies with large sample sizes, especially in the Chinese population. This study retrospectively evaluated the diagnostic value of a combined assay of five auto-antibodies [anti-cyclic citrullinated peptide (anti-CCP), anti-keratin (AKA), anti-RA 33, glucose-6-phosphate isomerase (GPI), and rheumatoid factor (RF)] for RA.Material/MethodsData were obtained from 5,725 patients with rheumatic diseases in Southwest Hospital of Chongqing from 2011 to 2014. Detection of the five serological markers was performed for all study patients using the appropriate method for each antibody.ResultsIt was found that of the 5,725 patients, the positive rates for RF, anti-CCP, anti-RA 33, AKA, and GPI were 52.5%, 40.1%, 12.8%, 12.0%, and 50.0% respectively. In RA patients, the positive rates were 83.3%, 68.5%, 16.6%, 20.8%, and 77.9% respectively, which were all significantly higher than those detected in patients with the other diseases (p<0.01). The areas under the receiver operator characteristic (ROC) curve for RF, anti-CCP, anti-RA 33, AKA, and GPI were 0.857, 0.831, 0.528, 0.602, and 0.822 respectively, indicating that these five serological markers display favorable diagnostic value for RA. There were positive correlations between anti-CCP antibody and RF and GPI (p<0.01) and between RF and GPI (p<0.01), but no correlation between anti-RA 33 and AKA (p<0.01). The specificity of the combination of anti-CCP, AKA, and GPI was 100% for RA diagnosis.ConclusionsThe combined assay of serological markers significantly improved the diagnostic specificity for RA. The diagnostic value of RF for RA was the highest and the combined assay for anti-CCP, AKA, and GPI had the highest specificity for RA diagnosis.

Neutralization-Enhancing RF Antibodies for HIV Vaccines.

Efficient neutralization of HIV is a primary goal both for therapeutic and prophylactic HIV vaccines based on induction of neutralizing antibodies (NAbs) (1, 2). Neutralization capacity of NAbs correlates with their affinity to HIV-1 gp120 envelope glycoprotein (3). In HIV-infected individuals, early IgM antibodies have low affinity for gp120 glycoprotein (3), which is slightly compensated by their pentameric structure and avidity to multivalent structures of the virus. Corresponding IgG1 antibodies (3, 4), which appear later from IgM through the CSR and SHM processes (3, 5), have high affinity and specificity to gp120, but low avidity due to monomeric structure of IgG. The question is how to induce HIVspecific NAbs with both high affinity and avidity to gp120? Anti-HIV IgG antibodies 2F5 and 2G12, switched back to IgM isotype, showed increased avidity and neutralization efficacy (2). Dendritic antibody supramolecules (DAS) in one molecule combine high specificity of IgG with high avidity of IgM (6). It would be of interest to construct such a DAS with IgM as a core, carrying 10 anti-gp120 IgG monomers. Natural monomeric anti-gp120 IgG1 antibodies (3, 4) not only have low avidity insufficient for effective neutralization of HIV but may also contribute to FcR-mediated infection enhancement (7, 8). Does it mean that HIV may use high-affinity IgG antibodies for its own purposes? Fortunately, in nature there exist some helpful network-like regulatory mechanisms with a key role of RF antibodies (9). Rheumatoid factor (RF) is an autoantibody which specifically binds Fc region of IgG (10, 11). Apart from pathologic RF in rheumatoid arthritis (12), natural RF appears in many non-rheumatoid states (13). Possible beneficial physiological roles of RF include enhanced clearance of immune complexes (ICs) (14), amplification of IgG response to pathogens (15), and enhancement of virus neutralization (16, 17). RF can be induced in vivo in a highly specific way either by secondary immunization with protein antigens or in response to immunization with the newly formed ICs (10, 11). New antigenic determinants, which appear in the Fc region of IgG antibody upon antibody-antigen complex formation, may strengthen the specificity of RF (9). The level of RF was significantly higher in some of HIV-infected individuals compared to control groups (18–22). RFs were mainly IgA, IgM immunoglobulins with specificity against anti-HIV IgG (20). RF-mediated enhancement of antiHIV IgG neutralization activity was found in the sera from MCTD patients (17). Authors suggested that RF is promising for passive immunotherapy based on NAbs (17). Can RF play a key role in specific enhancement of IgG-mediated neutralization of HIV in vivo? Measurements of RF level both in long-term non-progressors (23) and dual-infected individuals (24) might give some clues. Repeated immunization of uninfected macaques with HIV1 gp120 glycoprotein may allow researchers not only to track the kinetics of RF induction but also to elucidate whether neutralization-enhancing RF antibodies can protect macaques against subsequent challenge with SHIV. Repeated immunization of SHIV-infected macaques with HIV1 gp120 glycoprotein might show whether neutralization-enhancing RF antibodies can prolong the asymptomatic period and delay the onset of AIDS. The level of RF is not stable and has a tendency to decline during the acute phase of HIV infection (22). Prolonged repeated immunizations with gp120 (e.g., immunizations every 3 weeks; the actual time between immunizations will be adjusted according to measurements of RF level in patients) would be the solution to keep the level of neutralization-enhancing RF antibodies constantly high. Singleadministration vaccine (SAV) technology, which is based on pulsatile release of gp120 from biodegradable polymeric microspheres, mimics repeated immunization scheme, and allows vaccination to be done in one shot (25, 26). Patient-specific therapeutic HIV vaccines (1) even in simplified version, using the only one gp120 variant formed after completion of HIV population homogenization process (27), can be performed via repeated immunizations from biodegradable polymeric microspheres under SAV (25, 26) technology platform. Prophylactic HIV vaccines can be based on the variations of sequential scheme (28) for prolonged pulsatile release of gp120 glycoproteins from biodegradable polymeric microspheres in single-shot (25, 26) way convenient for both patients and doctors. Studies (15, 17) have shown the high potential of neutralization-enhancing RF antibodies, but several principal questions arise:

Diagnostic Performance of Tests for Anti-cyclic Citrullinated Peptides and Rheumatoid Factor in Rheumatoid Arthritis

Background: To compare the use of anti-cyclic citrullinated peptide antibodies (anti-CCPs) and rheumatoid factor (RF) in the diagnosis of rheumatoid arthritis (RA). Methods: Serum concentrations of anti-CCPs and RF were measured in 244 cases, including 39 patients with RA and 205 patients with other rheumatic diseases (non-RA). The age, sex, initial presentation, RF, anti-CCP results and the final diagnoses were recorded and analyzed. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) were calculated. Results: Among all 244 patients, 39 (15.2%) were diagnosed with RA and 205 (84.8%) were diagnosed with other rheumatic diseases (non-RA). Among the RA patients, 26 (67%) tested positive for RF, and 31 (79%) tested positive for anti-CCPs. RF was positive in 2 of 8 (25%) anti-CCP-negative patients with RA, and anti-CCP was positive in 7 of 13 (53.8%) RF-negative patients with RA. In the diagnosis of RA, the sensitivity, specificity, PPV, NPV, LR+ and LR- of the RF test were 67%, 79%, 37%, 93%, 3.11, and 0.42, respectively. The corresponding data for the anti-CCP test were 79%, 98%, 86%, 96%, 32.59, and 0.21, respectively. The presence of either anti-CCPs or RF increased the sensitivity to 84.6%, and when they both were present, the specificity increased to 98.1%. Conclusion: The RF and anti-CCP tests are complementary in the diagnosis of RA, and positivity in both tests improves the detection of RA. The results of the present study show that anti-CCPs had better sensitivity (79% vs. 67%) and better PPV (86% vs. 37%) than RF for the diagnosis of RA in our population. However, these two tests had similar NPVs (96% vs. 93%). In cases presenting with clinical symptoms or signs of RA but negative RF results, screening for anti-CCPs is still warranted.