RF-positive Patients Research Articles

THU0327 Radiological peripheral involvement at hands, feet and hips in young adults with polyarticular idiopathic juvenile arthritis

BackgroundRadiographic damage was recently considered to be a feature of poor prognosis in cases of polyarticular juvenile idiopathic arthritis (pJIA). However, most radiographic studies did not differentiate pJIA from other...

AB0271 Changes of serological markers in early and established rheumatoid arthritis (RA) during the course of traditional and biological disease modifying therapy

BackgroundRheumatoid factor (RF) and antibodies to citrullinated peptides (ACPA) are established markers in the diagnostic and prognostic approach to RA1. Several studies have examined changes of RF during therapy, but...

AB0455 Disease duration, but not rheumatoid factor status, impacts clinical response in adalimumab-treated rheumatoid arthritis patients with an inadequate response to standard dmard therapy: Subgroup analysis of the DE020 continuation trial

BackgroundRheumatoid factor (RF) is a prognostic marker of aggressive rheumatoid arthritis (RA); effective disease control may be more difficult in RF positive (+) patients (pts). Some biologic DMARDs have differential...

AB0113 Association between functional fc receptor-like 3 (fcrl3) -169 c/t polymorphism and susceptibility to seropositive rheumatoid arthritis: a meta-analysis

BackgroundThe Fc receptor-like 3 gene (FCRL3) is located on chromosome 1q21, a region implicated in susceptibility to several autoimmune diseases by whole-genome linkage studies. The FCRL3 protein is an orphan...

SAT0002 ACPA-negative rheumatoid arthritis consists of two genetically distinct subsets based on RF positivity

BackgroundHLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA) [1]. However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated...

AB0511 Rituximab in rheumatoid arthritis – interim analysis of the non-interventional bridging study

ObjectivesThe BRIDGING study collects clinical routine data on the efficacy and safety of rituximab (RTX) in patients suffering from severe active rheumatoid arthritis (RA).MethodsBRIDGING is a prospective, non-interventional study with...

SAT0090 Impact of rheumatoid factor and anti-CCP antibodies on eular response to long-term treatment with rituximab in patients with rheumatoid arthritis after failing one TNFI (first and refirst)

BackgroundReFIRST is an exploratory, multi-center, open label, uncontrolled phase IIIb study evaluating the efficacy of re-treatment with Rituximab (RTX). It is the extension of the FIRST study that included 302...

AB0366 Radiographic outcome in patients with early japanese rheumatoid arthritis receiving conventional dmards over 15 years of follow-up

BackgroundThe joint destruction in rheumatoid arthritis (RA) are well known to progress for an onset early stage. Therefore, the treatment intervention that is appropriate from an onset early stage is...

Association between -871C>T promoter polymorphism in the B-cell activating factor gene and the response to rituximab in rheumatoid arthritis patients

To determine whether a functional single-nucleotide polymorphism in the B-cell activating factor (BAFF) gene correlates with the response to treatment with rituximab (RTX) in RA. SMART is a randomized open trial (NCT01126541) assessing two strategies of re-treatment in patients responding to 1-g infusion of RTX with MTX on days 1 and 15 after failure, intolerance or contraindication to TNF blockers. Among the 224 patients included, 115 provided informed consent, could be genotyped and were included in an ancillary study of SMART assessing European League Against Rheumatism (EULAR) response rate after the first course of RTX according to BAFF-871C>T polymorphism. Baseline clinical factors (patients and disease characteristics) and biologic factors (ESR, CRP, RF, anti-citrullinated peptide antibodies, serum immunoglobulins) were collected. Univariate analyses were performed to assess whether BAFF-871C>T polymorphism was associated with EULAR response at week 24. Results with P < 0.15 obtained in univariate analyses were then included in multivariate analysis adjusted on DAS28 level. Ninety-three patients (81%) were responders, of whom 31 (27%) were good responders. CC genotype was significantly associated with a higher response rate [92% of responders vs 64% for TT genotype, odds ratio (OR) = 6.9; 95% CI 1.6, 29.6; P = 0.03]. These results were also confirmed in RF-positive patients (96% vs 58%, P = 0.006). In multivariate analysis, C allele carriage was independently associated with response to RTX (OR = 4.1; 95% CI 1.3, 12.7; P = 0.017). The BAFF-871C>T polymorphism seems to influence the response to RTX in RA patients after failure or intolerance to TNF blockers.

Performance of hands and feet radiographs in differentiation of psoriatic arthritis from rheumatoid arthritis

The purpose of this study was to determine useful radiographic findings for differentiating psoriatic arthritis (PsA) from rheumatoid factor (RF)-positive or -negative rheumatoid arthritis (RA) in Japanese patients. We accrued 85 patients with PsA. Controls included 135 patients with RA (85 RF-positive, 50 RF-negative) matched for gender and disease duration with PsA patients. Radiographs of hands and feet were obtained, and distal interphalangeal (DIP) erosive disease, joint osteolysis, tuft osteolysis, juxta-articular bony proliferation (JBP), periosteal new bone formation and bony ankylosis, which were identified using the definitions developed by an earlier study, were compared between the PsA and RA groups. For radiographic features of hands, the frequencies of JBP, periosteal new bone, and diffuse soft tissue swelling of the fingers were significantly higher in PsA patients than in RF-positive RA patients. However, only the frequency of JBP significantly differed between PsA and RF-negative RA patients. In feet, the frequencies of DIP erosive disease, tuft osteolysis, JBP, and diffuse soft tissue swelling of the toes were significantly higher in PsA patients than in RF-positive RA patients. However, only the frequency of JBP significantly differed between PsA and RF-negative RA patients. JBP was the most important radiographic feature for discriminating PsA from both RF-positive and -negative RA, confirming the study by the CASPAR group that showed that JBP is the only radiologic feature that can discriminate PsA from other inflammatory arthritides. This study showed the utility of plain radiographs for diagnosis of PsA.

ACPA-Negative RA Consists of Two Genetically Distinct Subsets Based on RF Positivity in Japanese

HLA-DRB1, especially the shared epitope (SE), is strongly associated with rheumatoid arthritis (RA). However, recent studies have shown that SE is at most weakly associated with RA without anti-citrullinated peptide/protein antibody (ACPA). We have recently reported that ACPA-negative RA is associated with specific HLA-DRB1 alleles and diplotypes. Here, we attempted to detect genetically different subsets of ACPA-negative RA by classifying ACPA-negative RA patients into two groups based on their positivity for rheumatoid factor (RF). HLA-DRB1 genotyping data for totally 954 ACPA-negative RA patients and 2,008 healthy individuals in two independent sets were used. HLA-DRB1 allele and diplotype frequencies were compared among the ACPA-negative RF-positive RA patients, ACPA-negative RF-negative RA patients, and controls in each set. Combined results were also analyzed. A similar analysis was performed in 685 ACPA-positive RA patients classified according to their RF positivity. As a result, HLA-DRB1*04:05 and *09:01 showed strong associations with ACPA-negative RF-positive RA in the combined analysis (p = 8.8×10−6 and 0.0011, OR: 1.57 (1.28–1.91) and 1.37 (1.13–1.65), respectively). We also found that HLA-DR14 and the HLA-DR8 homozygote were associated with ACPA-negative RF-negative RA (p = 0.00022 and 0.00013, OR: 1.52 (1.21–1.89) and 3.08 (1.68–5.64), respectively). These association tendencies were found in each set. On the contrary, we could not detect any significant differences between ACPA-positive RA subsets. As a conclusion, ACPA-negative RA includes two genetically distinct subsets according to RF positivity in Japan, which display different associations with HLA-DRB1. ACPA-negative RF-positive RA is strongly associated with HLA-DRB1*04:05 and *09:01. ACPA-negative RF-negative RA is associated with DR14 and the HLA-DR8 homozygote.

Evidence of fibrinogen as a target of citrullination in IgM rheumatoid factor-positive polyarticular juvenile idiopathic arthritis

Several studies have noted the significance of measuring anti-cyclic citrullinated peptide (CCP) antibodies in juvenile idiopathic arthritis (JIA) as an important indicator for destructive disease, as is the case in rheumatoid arthritis (RA). While the role of anti-CCP antibodies in RA and JIA has become better understood, the identity of the target proteins of this modification has remained elusive. In this study, we evaluated serum from patients with various subtypes of JIA to investigate the presence of anti-deiminated (citrullinated) fibrinogen and anti-citrullinated α-enolase antibodies, and their association with RF and anti-CCP antibody isotypes.Sera were obtained from 96 JIA patients, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. All sera were measured for antibodies against citrullinated and native fibrinogen and α-enolase by an enzyme linked immunosorbent assay (ELISA). In addition, all sera were assayed for anti-CCP antibody isotypes and rheumatoid factor (RF) isotypes by ELISA. The relationship between anti-citrullinated fibrinogen and anti-α-enolase antibodies and disease activity and joint damage were also investigated. All results were correlated with clinical and laboratory parameters using Spearman's rho correlation coefficient. Multiple logistic regression analysis was utilized to identify which variables were associated with joint erosions and diagnosis of JIA.Thirty-one JIA patients (32%) demonstrated reactivity to citrullinated fibrinogen and 9 (9%) to citrullinated α-enolase. Reactivity to citrullinated fibrinogen and α-enolase was predominantly found in IgM RF-positive polyarthritis patients. Fourteen JIA patients reacted with native α-enolase and a higher percentage of SLE patients reacted with citrullinated α-enolase when compared to JIA patients. Anti-citrullinated fibrinogen antibodies correlated with the presence of IgG anti-CCP antibodies and IgA and IgM RF. The presence of anti-citrullinated α-enolase antibodies correlated with IgA anti-CCP antibodies. IgG anti-CCP antibodies were significantly associated with joint damage and anti-citrullinated fibrinogen antibodies were strongly associated with JIA when compared to control groups. Anti-citrullinated fibrinogen antibodies demonstrated high sensitivity (81%) for IgM RF-positive polyarticular JIA. IgG anti-CCP antibodies had the highest specificity (95%) for JIA, with anti-citrullinated fibrinogen antibodies, IgA anti-CCP antibodies and IgA RF all following at 84%.JIA patient sera exhibited strong reactivity to anti-citrullinated fibrinogen antibodies and demonstrated high sensitivity and specificity for JIA, primarily in IgM RF-positive polyarthritis patients. Fibrinogen is one of several protein targets for citrullination in JIA.

Influence of BLK polymorphisms on the risk of rheumatoid arthritis

B cell lymphocyte kinase (BLK) encodes a member of the Src kinase family and thus may influence the proliferation and differentiation of cells. A single nucleotide polymorphism (SNP) located in the first intron of BLK has shown that the risk C allele of rs2248932 is associated with lower levels of messenger RNA expression of BLK. We hypothesized that this polymorphism may contribute to rheumatoid arthritis (RA) susceptibility. We studied BLK rs2248932 T/C gene polymorphisms in 329 patients with RA and 697 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). When the BLK rs2248932 TT homozygote genotype was used as the reference group, the CC genotype was associated with a significantly increased risk of RA. In the recessive model, when the BLK rs2248932 TT/TC genotypes were used as the reference group, the CC homozygote genotype was associated with a significantly increased susceptibility to RA. In stratification analyses, a significantly increased risk for RA associated with the BLK rs2248932 CC genotype was evident among younger patients, CRP-negative patients and anti-CCP-positive patients compared with the BLK rs2248932 TT/TC genotype. The risk was also significantly evident among RF-positive patients, patients with lower ESR levels, patients with lower or higher DAS28 score and patients with a lower functional class. These findings suggested that the functional SNP BLK rs2248932 T/C variant allele was associated with RA development. However, our results were obtained from a moderate-sized sample, and therefore this is a preliminary conclusion. Validation in a larger study from a more diverse ethnic population is needed to confirm these findings.

RF positivity has substantial influence on the peripheral memory B-cell compartment and its modulation by TNF inhibition

Objectives: The role of B cells in rheumatoid arthritis (RA) has been well established with the advent of B-cell targeted therapies. Alterations of peripheral B-cell subsets in RA and heterogeneous modulations of the B-cell compartment under tumour necrosis factor (TNF) inhibition have been described. In this study we examined the influence of rheumatoid factor (RF) positivity on the peripheral B-cell compartment and its modulation under TNF blockade.Methods: Consecutive patients with RA and inadequate response to methotrexate (MTX) were stratified according to RF status and a subset of them was included in a prospective study of weekly etanercept treatment.Results: At baseline, RF-negative patients had a significant higher percentage of overall CD27+ B cells compared to healthy controls (HC) and RF-positive patients. In detail, RF-negative patients had 46.6% (range 15.7–86.8%) CD27+ B cells compared to 31.3% (12.9–56.9%, p = 0.026) in HC and 29.8% (19–73.3%, p = 0.04) in RF-positive patients. Within the CD27+ compartment, CD27+/immunoglobulin (Ig)D+ memory B cells were significantly increased to 26.4% (range 5.9–54.7%) in RF-negative patients compared to 14.9% (4.1–27.3%, p = 0.006) in HC and 10.5% (3.4–41.1%, p = 0.003) in RF-positive patients. During anti-TNF therapy, memory B cells increased significantly in relative and absolute numbers only in RF-negative patients.Conclusions: In RF-negative patients, we observed an enhanced frequency of peripheral memory B cells and an accumulation of pre-switch memory B cells. During anti-TNF therapy, memory B cells increased significantly only in RF-negative patients, suggesting that the peripheral memory B-cell compartment is more amenable to TNF inhibition in these patients.

Efficacy of rituximab in the treatment of rheumatoid arthritis. Influence of serologic status, coprescription of methotrexate and prior TNF-alpha inhibitors exposure

PurposeRituximab has been shown to be efficient in the treatment of rheumatoid arthritis (RA) when associated with methotrexate (MTX). The purpose of this study was to evaluate the response to this treatment in daily practice in the following three specific situations: rheumatoid factor (RF)-negative RA patients, rituximab monotherapy patients and TNFα inhibitors-naive patients. MethodsThis retrospective observational study is an exploratory analysis of the response to rituximab. One thousand milligrams (1000mg) of rituximab was administered twice at an interval of 15 days. Therapeutic response was determined at mean 20 weeks after the infusion on the basis of DAS28 scores and EULAR response criteria. ResultsOne hundred and eight patients were included in the study and the responses of 95 of these were evaluated. Of the latter, 75% were EULAR responders. There was no significant difference in EULAR response between patients treated with rituximab and MTX (73.8%) and those who had received rituximab alone (79.3%). Similarly, there was no difference in the number of EULAR responders between patients who had received TNF inhibitor beforehand (74.1%) and those who had not (78.6%). However, interval to retreatment was significantly shorter in TNF inhibitor-naive patients. Lastly, a significant difference (P=0.02) in EULAR response rate was observed between RF-positive patients (84.8%) and RF-negative patients (57.9%). Interval to retreatment was also significantly shorter in RF-negative patients. ConclusionIn our experience, while our RTX efficacy findings appear to be consistent with the results of comparable controlled trials, whether or not in association with MTX, or with prior administration of one or several TNF inhibitors, RF-positive RA patients exhibited a higher EULAR response rate than RF-negative RA patients.

Rheumatoid factor positivity rather than anti-CCP positivity, a lower disability and a lower number of anti-TNFα agents failed are associated with response to rituximab in rheumatoid arthritis

Predictors of response to biologics in rheumatoid arthritis (RA) is an important issue in the current era. Rituximab (RTX) has been demonstrated effective and safe in active RA, resistant to traditional or biologic DMARDs. Fifty-seven patients with active longstanding RA were treated with RTX after traditional DMARD or anti-TNF alpha therapy failure. Number of anti-TNF treatment previously failed (p=0.005), HAQ (p=0.013), rheumatoid factor (RF) (p=0.0002) and anti-CCP (p=0.006) were associated with an ACR response > or =50 at the end of 6th month by univariate analysis. Multivariate analysis confirmed that the number of anti-TNF previously failed, baseline HAQ and RF, but not anti-CCP were associated with an ACR response > or =50. EULAR moderate/good response was associated with ESR value (p=0.036), HAQ (p=0.032), and RF (p=0.01) by univariate analysis, while only RF positivity was associated with EULAR moderate/good response by multivariate analysis. RF positivity rather than anti-CCP positivity is a predictor of response to RTX, suggesting that RF-positive patients with low disability may obtain a clinical response when treated to RTX after the first anti-TNF agent failure or after traditional DMARD therapies. Larger studies are required to confirm these results.

Evidence of fibrinogen as a target of citrullination in IgM rheumatoid factor-positive polyarticular juvenile idiopathic arthritis.

BackgroundSeveral studies have noted the significance of measuring anti-cyclic citrullinated peptide (CCP) antibodies in juvenile idiopathic arthritis (JIA) as an important indicator for destructive disease, as is the case in rheumatoid arthritis (RA). While the role of anti-CCP antibodies in RA and JIA has become better understood, the identity of the target proteins of this modification has remained elusive. In this study, we evaluated serum from patients with various subtypes of JIA to investigate the presence of anti-deiminated (citrullinated) fibrinogen and anti-citrullinated α-enolase antibodies, and their association with RF and anti-CCP antibody isotypes.MethodsSera were obtained from 96 JIA patients, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. All sera were measured for antibodies against citrullinated and native fibrinogen and α-enolase by an enzyme linked immunosorbent assay (ELISA). In addition, all sera were assayed for anti-CCP antibody isotypes and rheumatoid factor (RF) isotypes by ELISA. The relationship between anti-citrullinated fibrinogen and anti-α-enolase antibodies and disease activity and joint damage were also investigated. All results were correlated with clinical and laboratory parameters using Spearman's rho correlation coefficient. Multiple logistic regression analysis was utilized to identify which variables were associated with joint erosions and diagnosis of JIA.ResultsThirty-one JIA patients (32%) demonstrated reactivity to citrullinated fibrinogen and 9 (9%) to citrullinated α-enolase. Reactivity to citrullinated fibrinogen and α-enolase was predominantly found in IgM RF-positive polyarthritis patients. Fourteen JIA patients reacted with native α-enolase and a higher percentage of SLE patients reacted with citrullinated α-enolase when compared to JIA patients. Anti-citrullinated fibrinogen antibodies correlated with the presence of IgG anti-CCP antibodies and IgA and IgM RF. The presence of anti-citrullinated α-enolase antibodies correlated with IgA anti-CCP antibodies. IgG anti-CCP antibodies were significantly associated with joint damage and anti-citrullinated fibrinogen antibodies were strongly associated with JIA when compared to control groups. Anti-citrullinated fibrinogen antibodies demonstrated high sensitivity (81%) for IgM RF-positive polyarticular JIA. IgG anti-CCP antibodies had the highest specificity (95%) for JIA, with anti-citrullinated fibrinogen antibodies, IgA anti-CCP antibodies and IgA RF all following at 84%.ConclusionsJIA patient sera exhibited strong reactivity to anti-citrullinated fibrinogen antibodies and demonstrated high sensitivity and specificity for JIA, primarily in IgM RF-positive polyarthritis patients. Fibrinogen is one of several protein targets for citrullination in JIA.

Effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA)

ObjectivesTo confirm the effectiveness and safety of the interleukin 6-receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) in a setting close to real-life medical care in Germany.MethodsA multicentre open-label...

Disease Activity, Smoking, and Reproductive-related Predictors of Poor Prognosis in Patients with Very Early Inflammatory Polyarthritis

To identify disease activity, smoking, and reproductive-related predictors of a poor prognosis in patients with very early inflammatory polyarthritis (IP). Patients with very early IP (symptom duration 4-11 weeks) included in our study were participants in the STIVEA (Steroids In Very Early Arthritis) randomized placebo-controlled trial. At baseline, disease-related variables were measured and patients were asked to complete a questionnaire covering smoking status and reproductive questions. Baseline predictors of poor prognosis [i.e., the need to start disease-modifying antirheumatic drug (DMARD) therapy by 6 months or the clinical diagnosis of rheumatoid arthritis (RA) at 12 months] were identified, applying logistic regression analyses adjusted for treatment group. Rheumatoid factor (RF) positivity was one of the strongest clinical predictors of a poor prognosis: OR for DMARD therapy at 6 months, 4.00 (95% CI 2.00-8.00) and OR for a diagnosis of RA at 12 months, 9.48 (95% CI 4.48-20.07). There was a significant association between current smoking at baseline compared to never smoking and a diagnosis of RA at 12 months (OR 3.15, 95% CI 1.16-8.56). About 6 in 7 patients with very early RF-positive IP were diagnosed with RA 1 year later. In addition, 1 in 4 IP patients who smoke will develop RA later. It is recommended to treat RF-positive patients who have IP with DMARD at presentation and to advise patients to stop smoking.

Rheumatoid arthritis and heart disease: the chicken and the egg?

Rheumatoid arthritis and heart disease: the chicken and the egg?