RF-negative Patients Research Articles

The Frequency of anti-CCP antibodies in patients with rheumatoid arthritis and psoriatic arthritis and their relationship with clinical features and parameters of angiogenesis: A comparative study.

Macrophage migration inhibitory factor (MIF) and vascular endothelial growth factor (VEGF), as crucial parameters of angiogenesis and inflammation, were evaluated to identify the role of cyclic citrullinated peptide antibodies (anti-CCP) during angiogenesis in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). A total of 145 patients with RA, 44 patients with PsA, and 73 healthy subjects were included in this study. The clinical features, total blood counts, and acute phase parameters of RA and PsA patients were recorded. Anti-CCP antibody, VEGF, and MIF levels were determined with enzyme-linked immunosorbent assay (ELISA). Anti-CCP positivity was significantly higher in the RA group (69%) than in both PsA (20.6%) and controls (8.2%) (p values<0.001). There was no difference between anti-CCP-positive and -negative RA patients regarding the extra-articular manifestations (p>0.05). VEGF and MIF levels were similar in anti-CCP-positive and -negative RA patients (all p values>0.05). The specificity of anti-CCP antibodies for RA was found to be 87.2%. No relationship was found between anti-CCP antibody positivity and clinical features, disease activity, functional disability as assessed by health assessment questionnaire scores, and extra-articular manifestations. There was no relationship between parameters of angiogenesis and anti-CCP antibody positivity. Both RF and anti-CCP antibodies were observed to be positive in most patients with RA. Either RF or anti-CCP antibody was positive in a considerable proportion of our RA patients. Therefore, anti-CCP antibodies are important in the diagnosis of RF-negative patients who present with clinical findings of RA.

Whole blood gene expression profiling predicts therapeutic response at six months in patients with polyarticular juvenile idiopathic arthritis.

ObjectiveTo determine whether gene expression profiles identified in peripheral whole blood samples could be used to determine therapeutic outcome in a cohort of children with newly diagnosed polyarticular juvenile idiopathic arthritis (JIA).MethodsWhole blood samples from the Trial of Early Aggressive Therapy (TREAT) in JIA patients were analyzed on Illumina microarrays, and differential gene expression was compared to expression in healthy controls. Microarray results were validated by real-time quantitative polymerase chain reaction in an independent cohort of samples. Pathway analysis software was used to characterize gene expression profiles. Support vector machines were used to develop predictive models for different patient classes.ResultsDifferential gene expression profiles for rheumatoid factor (RF)–positive and RF-negative patients were remarkably similar. Pathway analysis revealed a broad range of affected pathways, consistent with current mechanistic theories. Modeling showed that the prognosis at 6 months was strongly linked to gene expression at presentation, irrespective of treatment.ConclusionGene expression is linked to therapeutic outcome, and gene expression in the peripheral blood may be a suitable target for a prognostic test.

A1.29 In rheumatoid arthritis, smoking is not primarily associated with anti-citrullinaged protein antibodies, but with the presence of several autoantibodies

Background and ObjectivesIn rheumatoid arthritis (RA), smoking has been described to be specifically associated with the presence of anti-citrullinated protein antibodies (ACPA). However, smoking has also been shown to be...

Anti-Mutated Citrullinated Vimentin (Anti-MCV) Antibodies as a Diagnostic Aid for Rheumatoid Arthritis

Background: This study aimed to evaluate the role of anti-MCV antibodies in the diagnosis of RA and correlate anti-MCV with other markers of disease activity. Subjects and methods: The study was carried out on 70 individuals, categorized as follows; 40 patients diagnosed as rheumatoid arthritis (RA) (Group I), 15 patients diagnosed as osteoarthritis disease (OA) (Group II) and their results were compared to 15 apparently healthy persons as control group (Group III). All participants were subjected to careful history taking, general examination, routine laboratory investigations, in addition to, anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) assays. Results: Anti-CCP and anti-MCV values were significantly higher in group I when compared to group II and III (Pvalue 27.5 U/ml at which Sensitivity was 99.1, Specificity was 93.3, PPV was 97.8 and NPV was 99.8. The AUC (area under the curve) value for anti-MCV was 0.997. There were highly significant positive correlations between anti-MCV, anti-CCP and ESR in group I (P-value<0.001 and 0.001). Anti-CCP and anti-MCV were significantly higher in RF positive patients compared to RF negative patients (P-values=0.005 and 0.011 respectively), while no significant differences in anti-CCP and anti-MCV were found between CRP positive and CRP negative patients in group I. Conclusion: Anti-MCV is an excellent marker for early diagnosis of RA with high sensitivity and specificity especially when other markers are negative. The use of anti-MCV and anti-CCP collectively give the best result for the diagnosis of rheumatoid disease.

Renal Enzymes and Microglobulins in Patients with Rheumathoid Arthritis

Aim: The aim of this study was to detect and compare the enzymes, globulins and reactants of the early phase in patients with untreated rheumatoid arthritis and to reveal the effect of untreated rheumatoid arthritis on tubular function and sensitivity on brush border area. Material and Methods: The samples of serum and urine were examined in 70 participants (35 patients with untreated rheumatoid arthritis, 35 individuals of the healthy control group). We used in the study the kinetic assay for determination of alanine aminopeptidase (AAP) (Standards methods under IFCC), γ-glutamiytransferase and MEIA (Microparticle Enzyme Immunoassay) (Abbot Axsym system) for detection of β 2-microglobulin in urine. Results: Of 35 patients with RA, 16 patients showed presence of γ-GT (sensitivity of the test - 45.71%), 24 patients showed presence of AAP enzymuria (sensitivity of the test - 68.57%), while the presence of β2-microglobulin in urine was very low (sensitivity of the test - 0%). From 18 RF negative patients, 14 patients were AAP positive, 10 patients were γ-GT positive, while the presence of β2-microglobulin in urine was not detected. Among 17 RF positive patients with RA, the presence of AAP was detected in 10 patients, the presence of γ-GT in 6 patients, while the presence of β2-microglobulin in urine was not detected. Conclusion: In untreated rheumatoid arthritis AAP had higher sensitivity than γ-GT and β2-microglobulin in detection of asymptomatic renal damage

Association between functional Fc receptor-like 3 (FCRL3) −169 C/T polymorphism and susceptibility to seropositive rheumatoid arthritis in Asians: A meta-analysis

The aim of this study was to determine whether the functional Fc receptor like-3 (FCRL3) -169 C/T polymorphism confers susceptibility to rheumatoid arthritis (RA). A meta-analysis was conducted on the associations between the FCRL3 -169 C/T polymorphism and RA. A total of 17 comparison studies including 11,170 patients and 11,142 controls were considered in the meta-analysis. The meta-analysis showed no association between RA and the FCRL3 -169 C allele in study subjects (OR = 1.046, 95% CI = 0.997-1.098, p = 0.068). Stratification by ethnicity indicated an association between the FCRL3 -169 C allele and RA in Asians (OR = 1.101, 95% CI = 1.035-1.174, p = 0.002), but not in Europeans. Stratification of patients according to the presence of rheumatoid factor (RF) revealed a different significant association between the C allele and RA in RF-positive and RF-negative RA patients. Stratification by ethnicity indicated an association between the FCRL3 -169 C allele and RF-positive RA in Asians (OR = 1.093, 95% CI = 1.004-1.189, p = 0.040), but not in Europeans. This meta-analysis demonstrates that the FCRL3 -169 C/T polymorphism may confer susceptibility to seropositive RA in Asians.

AB0300 Efficacy of rituximab in the treatment of rheumatoid arthritis in moroccan patients tnf alpha inhibitor-naive: a prospective study

BackgroundThe emergence of publications about the role of B cells in the immunopathogenesis of rheumatoid arthritis (RA) has generated interest in the use of rituximab to treat RA. Several studies...

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...

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...

OP0190 Smoking is Not Primarily Associated with ACPA, but with the Presence of Multiple Autoantibodies in RA

BackgroundSmoking is associated with the presence of autoantibodies in various diseases, such as chronic obstructive pulmonary disease (COPD)1, systemic lupus erythematosus (SLE)2 and polymyositis3. In rheumatoid arthritis (RA), smoking is...

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...

Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a Chinese population

AimRheumatoid arthritis (RA) and ankylosing spondylitis (AS) are common systemic autoimmune diseases with genetic and environmental predisposing factors. Signal transducer and activator of transcription 4 (STAT4) transmits signals induced by interleukin-12, interleukin-23 and interferon-γ, which are key cytokines and play important roles in the development of autoimmune diseases. Previous studies confirmed the STAT4 rs7574865 G/T locus to be associated with RA. Thus we conducted a replication study to investigate STAT4 rs7574865 G/T polymorphism and RA/AS susceptibility in a Chinese population. MethodsWe studied STAT4 rs7574865 G/T gene polymorphism in 520 patients with RA, 100 AS patients and 520 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). ResultsWhen the STAT4 rs7574865 GG homozygote genotype was used as the reference group, the GT or GT/TT genotypes were associated with the risk for RA. After stratification analyses, a significantly increased risk for RA associated with the STAT4 rs7574865 GT genotype was evident among the rheumatoid factor (RF)-positive patients, patients with higher erythrocyte sedimentation rate (ESR) level and patients with higher RA disease activity score (DAS28) compared with the STAT4 rs7574865 GG genotype. A significantly increased risk for RA associated with the STAT4 rs7574865 TT genotype was evident among older patients and RF-negative patients compared with the STAT4 rs7574865 GG genotype. STAT4 rs7574865 G/T was not associated with susceptibility to AS. ConclusionThis replication study confirmed that STAT4 rs7574865 G/T polymorphism was associated with the risk of RA. Condensed abstractSTAT4 polymorphisms are associated with rheumatoid arthritis risk.

Superior performance of the CCP3.1 test compared to CCP2 and MCV in the rheumatoid factor-negative RA population

Anti-citrullinated protein/peptide antibodies (ACPAs) have recently been identified as sensitive and specific diagnostic and prognostic markers in rheumatoid arthritis (RA). In this study, we wished to assess the diagnostic performance of the third-generation anti-CCP3.1 assay, but with special focus on the rheumatoid factor (RF)-negative RA population. Anti-CCP as well as anti-MCV was tested in 119 RA patients and 118 control patients using second and third-generation assays. Using these optimal cut-off levels, the diagnostic sensitivity of anti-CCP2, CCP3, and CCP3.1 was 74.8, 78.8, and 83.0%, respectively, while the specificity was 95.7, 96.6, and 98.3%, respectively. The diagnostic performance of the CCP3.1 test was significantly better than that of CCP2 (p = 0.041). In addition, the CCP3.1 test performed significantly better than the MCV test as well (p = 0.0003). When the diagnostic performance of the CCP3.1, CCP2, and MCV tests was compared in the 35 RF-negative patients, the CCP3.1 test exerted significantly better performance than the MCV test (p = 0.006), and it also showed a tendency of better performance in comparison with the CCP2 test (p = 0.131). In conclusion, the CCP3.1 assay can significantly increase the sensitivity of ACPA testing in RF-negative RA, as well as in the total RA population.

The PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis

The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. MEDLINE database and manual search were utilized to identify articles in which the PTPN22 polymorphism was determined in RA patients and controls. A meta-analysis was conducted on the associations between the PTPN22 C1858T polymorphism and RA using (1) allelic contrast and (2) dominant model. A total of 30 separate comparisons involving 17,961 RA patients and 18,611 controls were considered in this meta-analysis. Meta-analysis showed an association between the T allele and RA in all subjects (OR = 1.490, 95% CI = 1.332-1.668, P < 1.0 × 10(-9)). After stratification by ethnicity, analysis indicated that the T allele was significantly associated with RA in Europeans and in Non-Europeans (OR = 1.423, 95% CI = 1.260-1.605, P = 1.0 × 10(-8); OR = 1.902, 95% CI = 1.488-2.430, P = 2.8 × 10(-8)). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and RF-negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF (OR = 1.561, 95% CI = 1.373-1.775, P < 1.0 × 10(-9)). This meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF-positive patents than in RF-negative patients.

Infliximab in Russian clinical practice

The study of infliximab began (INF) in Russia in 2001. It was the first genetically engineered biological agent (GEBA) registered in our country to treat patients with rheumatoid arthritis (RA). With the advent of infliximab, a Russian biological rheumatoid arthritis therapy registry started its work. In October 2005, it was set up on the basis of GEBA centers founded in the leading rheumatology clinics of Russia. Objective: to generalize the Russian experience in using INF (its efficacy, tolerance, and side effects) in patients with RA in real clinical practice within the framework of a multicenter observational study. Subjects and methods. The register included patients with a valid diagnosis of RA in whom INF treatment was first started. The main indication for this was previous basic therapy failure. This investigation analyzed 396 patients receiving INF therapy. Prior to INF administration, all the patients were examined to identify whether they had possible latent tuberculosis, by applying chest X-ray study and Mantoux test. The European League Against Rheumatism criteria were used to evaluate the efficiency of INF therapy. The relationship between the therapeutic effects of the drug and its cumulative dose was specially used. The trend in X-ray progression was estimated using the Sharp method modified by van der Heijde. INF was given in a dose of 3 mg/kg by the classical regimen: at 0, 2, and 6 weeks, then every 8 weeks. The main assessment periods were at 22 and 46—54 weeks. Results. Analysis of the data of real clinical practice in Russia demonstrates that the use of INF in RA patients with the inadequate effect of traditional disease-modifying antirheumatic drugs (DMARDs) is able to cause a rapid and pronounced reduction in disease activity. There is significant evidence that the IFN-treated patients with RA had also suppressed bone destruction. INF treatment for early RA gives rise to remissions more frequently in the early stage of therapy than that for extensive-stage disease. INF was shown to have a clear dose-dependent effect: in the patients receiving more than 4 infusions of the drug, bone destruction was more noticeably suppressed than in those having its fewer infusions. In most cases, suppressed destruction was accompanied by clinical improvement. A significant therapeutic effect was seen when both an annual course of INF and average (5—7 infusions per year) doses of the drug were used. The results of the analysis suggest that the probable efficiency of INF therapy increases in RF-negative patients with lower baseline RA activity and fewer HAQ scores. INF was quiet satisfactorily tolerated and caused no unusual side effects. Conclusion. The Russian experience in using INF strongly suggests that it is effective in real practice in severe RA resistant to therapy with traditional DMARDs.

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.

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.