ACPA-positive Rheumatoid Arthritis Research Articles

Exposure to passive smoking and rheumatoid arthritis risk: results from the Swedish EIRA study.

IntroductionSmoking has consistently been associated with increased risk of developing rheumatoid arthritis (RA). The aim of this study was to estimate the influence of passive smoking on the risk of developing anti-cyclic citrullinated peptide antibodies (ACPA)-positive and ACPA-negative RA.MethodsA population-based case–control study using incident cases of RA was performed in Sweden, and the study population in this report was restricted to include never-smokers (589 cases, 1764 controls). The incidence of RA among never-smokers who had been exposed to passive smoking was compared with that of never-smokers who had never been exposed, by calculating the OR with a 95% CI employing logistic regression.ResultsNo association was observed between exposure to passive smoking and RA risk (OR 1.0, 95% CI 0.8 to 1.2 for ACPA-positive RA, and OR 0.9, 95% CI 0.7 to 1.2, for ACPA-negative RA). No suggestion of a trend between duration of passive smoking and RA risk was observed.DiscussionsNo association was observed between exposure to passive smoking and RA risk, which may be explained by a threshold below which no association between smoke exposure and RA occurs.

ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis

ObjectivesPatients with autoantibody-positive rheumatoid arthritis (RA) are less likely to experience pregnancy-induced improvement of RA disease activity (DAS28-C reactive protein (CRP)) compared with patients with autoantibody-negative RA. Anti-citrullinated protein antibodies...

Biomechanical properties of bone are impaired in patients with ACPA-positive rheumatoid arthritis and associated with the occurrence of fractures

ObjectivesBone loss is a well-established consequence of rheumatoid arthritis (RA). To date, bone disease in RA is exclusively characterised by bone density measurements, while the functional properties of bone in...

Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis.

Neutrophil extracellular traps (NETs) comprise a unique form of non-apoptotic cell death exhibited by neutrophils, which occurs in a stepwise process termed NETosis. It has been postulated that NETosis plays an important role in the pathogenesis of autoimmune disorders. The aim of this study was to evaluate serum levels of NET remnants in patients with rheumatoid arthritis (RA), as well as potential associations between NET remnants and indicators of RA. Serum levels of myeloperoxidase (MPO)-DNA complexes (NET remnants) were examined in 74 RA patients and 50 healthy controls using a modified enzyme-linked immunosorbent assay. Associations between the levels of these complexes and indicators of RA were then statistically evaluated. RA patients exhibited significantly higher levels of MPO-DNA complexes than the healthy controls, and these levels were associated with increased neutrophil counts and positivity for rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA). Among the 63 ACPA-positive RA patients examined, those with ACPA titers > 1600 U/mL showed significantly increased MPO-DNA levels. Receiver operating characteristic analysis determined that the area under the curve for all 74 RA patients was 0.798, with a sensitivity of 91.9% and a specificity of 56.0%, while that for the ACPA-negative patients was 0.891, with a sensitivity and specificity of 81.8% and 84.0%, respectively. The results of this study suggest that the disease status of RA is associated with increased NETosis. In particular, evaluation of serum MPO-DNA levels may comprise a useful complementary tool for discriminating RA patients from healthy individuals.

Anticitrullinated protein/peptide antibody multiplexing defines an extended group of ACPA-positive rheumatoid arthritis patients with distinct genetic and environmental determinants

IntroductionThe second generation anticycliccitrullinated peptide (anti-CCP2) assay detects the majority but not all anticitrullinated protein/peptide antibodies (ACPA). Anti-CCP2-positive rheumatoid arthritis (RA) is associated with HLA-DRB1* shared epitope (SE) alleles and...

Low levels of antibodies against common viruses associate with anti-citrullinated protein antibody-positive rheumatoid arthritis; implications for disease aetiology

BackgroundInfection by common viruses has long been discussed in the aetiology of a number of autoimmune diseases, including rheumatoid arthritis (RA). However, studies investigating this hypothesis in RA show conflicting results. These studies often lack well-matched control populations, and many do not include data on autoantibodies, genetic risk factors and other environmental factors, which are known to contribute to disease only in subgroups of patients. In the present study, we have therefore examined the role of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and parvovirus B19 (B19) in RA aetiology, by analysing anti-viral antibodies in relation to anti-citrullinated protein antibodies (ACPA), smoking, HLA-DRB1 shared epitope (SE) alleles, and clinical parameters, in both RA patients and matched controls.MethodsAnti-viral antibodies were measured by ELISA in serum samples from 990 RA patients and 700 controls from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort. Data on ACPA, smoking, SE, inflammation (C-reactive protein) and disease activity score in 28 joints (DAS28) was obtained from the EIRA database. Fisher’s exact test, the chi-squared test, and the Mann-Whitney U test were used to calculate differences in anti-viral antibody frequencies and levels; unconditional logistic regression was used to determine the association of anti-viral antibodies with different RA subsets.ResultsAntibodies against all viruses were highly prevalent in EIRA, with no major differences detected between ACPA-positive RA, ACPA-negative RA and controls. However, both anti-B19 and anti-EBV IgG levels were significantly lower in ACPA-positive RA compared to controls, and there were significant interactions between low levels of anti-B19 and anti-EBV antibodies and SE in the development of ACPA-positive RA.ConclusionWe could not detect an association between RA and elevated anti-viral antibody levels, for any of the three common viruses, EBV, CMV or B19. On the contrary, our study demonstrated association between low anti-EBV/anti-B19 antibody levels and ACPA-positive RA, in particular when HLA-DRB1 SE was present. These data could potentially suggest that high anti-viral antibody levels would be protective against ACPA-positive RA. Further investigations are required to address the mechanisms behind these findings.

A mode of error: Immunoglobulin binding protein (a subset of anti-citrullinated proteins) can cause false positive tuberculosis test results in rheumatoid arthritis

Citrullinated Immunoglobulin Binding Protein (BiP) is a newly described autoimmune target in rheumatoid arthritis (RA), one of many cyclic citrullinated peptides(CCP or ACPA). BiP is over-expressed in RA patients causing T cell expansion and increased interferon levels during incubation for the QuantiFERON-Gold tuberculosis test (QFT-G TB). The QFT-G TB has never been validated where interferon is increased by underlying disease, as for example RA.Of ACPA-positive RA patients (n = 126), we found a 13% false-positive TB test rate by QFT-G TB. Despite subsequent biologic therapy for 3 years of all 126 RA patients, none showed evidence of TB without INH. Most of the false-positive RA patients after treatment with biologic therapy reverted to a negative QFT-G test. False TB tests correlated with ACPA level (p < 0.02).Three healthy women without arthritis or TB exposure had negative QFT-G TB. In vitro, all three tested positive every time for TB correlating to the dose of BiP or anti-BiP added, at 2 ug/ml, 5 ug/ml, 10 ug/ml, and 20 ug/ml.BiP naturally found in the majority of ACPA-positive RA patients can result in a false positive QFT-G TB. Subsequent undertreatment of RA, if biologic therapy is withheld, and overtreatment of presumed latent TB may harm patients.

Oral contraceptives, breastfeeding and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study

ObjectivesTo study whether oral contraceptive (OC) use or breastfeeding (BF) influence the risk of rheumatoid arthritis (RA), stratifying the cases by presence/absence of anticitrullinated protein antibodies (ACPA), and whether these...

Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis

ObjectiveThe pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common...

Incidence of inflammatory joint diseases in Finland: results from a population-based epidemiological study

The objective of the study was to assess the incidence of inflammatory joint diseases and possible environmental factors contributing to their occurrence in a defined population in Finland. All rheumatologists practising in the Northern Savo rheumatological outpatient departments collected data on their newly diagnosed patients with an inflammatory joint disease in 2010. Antibodies to Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg) were determined from patients with various arthritides. The incidence of all arthritis cases was 141.8/100,000 (95% CI 126.1-159.1). Eighty-six patients, 43 men and 43 women, satisfied the ACR/Eular 2010 classification criteria for rheumatoid arthritis (RA) yielding an annual incidence of 41.6/100,000 (33.3-51.4), 42.5 (30.8-57.3) for men and 40.8 (29.9-56.1) for women. The incidence of chronic spondyloarthritides was 36.3 (28.6-45.5), reactive arthritis 7.8 (4.4-12.6), undifferentiated arthritis 38.7 (30.7-48.2), and crystalline arthritis 15.0 (10.2-21.3). Immunoglobulin A (IgA) antibody levels to Pg were higher among men, patients with anti-cyclic citrullinated peptide antibodies (ACPA) or missing teeth and AaIgA antibody levels in patients with missing teeth. In RA, 67 % of men and 35% of women had a smoking history, p=0.012. There was no difference between the genders in the incidence of RA, which might be explained by a higher carriage of periodontal bacteria and a higher smoking rate among men. In other disease categories, the incidences were comparable to those earlier reported. By influencing behavioral and environmental factors, it might be possible to reduce the burden of ACPA-positive RA.

Relationship between shift work and the onset of rheumatoid arthritis

BackgroundEnvironmental factors play a prominent role in rheumatoid arthritis (RA) aetiology. Shift work has previously been associated with increased RA risk in females. The aim of this study was to...

Working in cold environment and risk of developing rheumatoid arthritis: results from the Swedish EIRA case–control study

ObjectivesTo investigate (1) whether working in cold environment (WCE) is associated with an increased risk of developing rheumatoid arthritis (RA) (overall), anticitrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA and...

The Economic Burden of ACPA-Positive Status Among Patients with Rheumatoid Arthritis.

Anticitrullinated protein antibodies (ACPAs) are serological biomarkers associated with early, rapidly progressing rheumatoid arthritis (RA), including more severe disease and joint damage. ACPA testing has become a routine tool for RA diagnosis and prognosis. Furthermore, treatment efficacy has been shown to vary by ACPA-positive status. However, it is not clear if the economic burden of patients with RA varies by ACPA status. To determine if the economic burden of RA varies by patient ACPA status. IMS PharMetrics Plus health insurance claims and electronic medical record (EMR) data from 2010-2015 were used to identify patients with incident RA. Patients were aged ≥ 18 years, had ≥ 1 inpatient or ≥ 2 outpatient claims reporting an RA diagnosis code (ICD-9-CM code 714.0), and had an anticyclic citrullinated peptide (anti-CCP; a surrogate of ACPA) antibody test within 6 months of diagnosis. Incident patients were defined as those who had no claims with an RA diagnosis code in the 6 months before the first observed RA diagnosis. The primary outcome of interest was RA-related medical expenditures, defined as the sum of payer- and patient-paid amounts for all claims with an RA diagnosis code. Secondary outcomes included health care utilization metrics such as treatment with a disease-modifying antirheumatic drug (DMARD) and physician visits. Generalized linear regression models were used for each outcome, controlling for ACPA-positive status (defined as anti-CCP ≥ 20 AU/mL), age, sex, and Charlson Comorbidity Index score as explanatory variables. Of 647,171 patients diagnosed with RA, 89,296 were incident cases, and 47% (n = 42,285) had an anti-CCP test. After restricting this sample to patients with a linked EMR and reported anti-CCP test result, 859 remained, with 24.7% (n = 212) being ACPA-positive. Compared with ACPA-negative patients, adjusted results showed that ACPA-positive patients were more likely to use either conventional (71.2% vs. 49.6%; P < 0.001) or biologic (20.3% vs. 11.8%; P < 0.001) DMARDs during the first year after diagnosis and had more physician visits (5.58 vs. 3.91 times per year; P < 0.001). Annual RA-associated total expenditures were $7,941 for ACPA-positive and $5,243 for ACPA-negative patients (Δ = $2,698; P = 0.002). RA-associated medical expenditures were $4,380 for ACPA-positive and $3,427 for ACPA-negative patients (Δ = $954; P = 0.168), whereas DMARD expenditures were $3,560 and $1,817, respectively (Δ = $1,743; P = 0.001). RA-related economic burden is higher for patients who are ACPA-positive compared with those who are ACPA-negative. Providers may wish to inform patients diagnosed with ACPA-positive RA about the likely future disease and economic burden in hopes that both stakeholders can be more proactive in addressing them. Funding for this research was contributed by Bristol-Myers Squibb. Patel and Price are employees and stockholders of Bristol-Myers Squibb. Shafrin and Tebeka are employees of Precision Health Economics, a health care consulting firm that received funding from Bristol-Myers Squibb to conduct this study. Michaud has received a grant from Pfizer and is employed by the National Data Bank for Rheumatic Diseases, which has received funds from Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, and Regeneron. Study concept and design were contributed by Shafrin, Price, Patel, and Michaud. Shafrin, Price, and Patel collected the data, and all authors contributed equally to data analysis. The manuscript was written by Shafrin and Tebeka and revised by Shafrin, Price, Patel, and Michaud.

Influence of Cigarette Smoking on Rheumatoid Arthritis Risk in the Han Chinese Population.

Cigarette smoking has been shown in European populations to be associated with rheumatoid arthritis (RA) susceptibility. This study aims to examine the association of smoking with RA in the Han Chinese population. 718 Han Chinese RA patients and 404 healthy controls were studied. The associations of cigarette smoking (current, former or ever vs. never smokers, and pack-years of exposure) with RA, anti-cyclic citrullinated peptide antibody (ACPA) positive RA, IgM rheumatoid factor (RF) positive RA, and baseline radiographic erosions (modified van der Heijde-Sharp scores) were assessed. The interaction between smoking and the HLA-DRB1 shared epitope (SE) in RA was also examined. In this study, 11 (1.53%) cases and 6 (1.49%) controls were former smokers (p = 0.95), while 95 (13.23%) cases and 48 (11.88%) controls were current smokers (p = 0.52). Trends toward associations between smoking status (ever vs. never) with RA-overall (p = 0.15, OR = 1.44), ACPA-positive RA (p = 0.24, OR = 1.37), RF-positive RA (p = 0.14, OR = 1.46), or the presence of radiographic erosions (p = 0.66, OR = 1.28) were observed although individually here were not statistically significant. There was no evidence of statistical interaction between smoking status (ever vs. never) and SE for all RA, ACPA-positive RA, ACPA-negative RA, RF-positive RA, RF-negative RA (p = 0.37, 0.50, 0.24, 0.26, and 0.81 respectively), and the 95% CI for the attributable proportion for all interactions included 0. This is the first study to examine the association of cigarette smoking with RA in the Han Chinese population. This study shows a trend toward an interaction between smoking and SE carriage influencing the risk of RA, though findings were not statistically significant. It is possible that in the presence of universal exposure to heavy air pollution the effect of smoking on RA risk may be obscured.

Differences in the symptomatic phase preceding ACPA-positive and ACPA-negative RA: a longitudinal study in arthralgia during progression to clinical arthritis

ObjectiveAlthough anticitrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis (RA) have different aetiopathology, the clinical presentation at the time of diagnosis is similar. This study evaluated whether there are phenotypic...

DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis

BackgroundMultiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA.MethodsWe investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA). Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA.ResultsWe identified and replicated one significant gene-environment interaction between rs6933349 and smoking in DNA methylation of cg21325723. This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicative P value = 0.056; additive P value = 0.016) and Asian populations (multiplicative P value = 0.035; additive P value = 0.00027), and it is mediated through DNA methylation of cg21325723.ConclusionsWe showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors.

FLT-1 gene polymorphisms and protein expression profile in rheumatoid arthritis.

ObjectivesInflammation and angiogenesis are a significant element of pathogenesis in rheumatoid arthritis (RA). The FLT-1- triggering factor for production of proinflammatory cytokines-might contributes to inflammation in patients with RA. Association of the FLT-1 polymorphisms with different “angiogenic diseases” suggests that it may be a novel genetic risk factor also for RA. The aim of the study was to identify FLT-1 genetic variants and their possible association with sFLT-1 levels, susceptibility to and severity of RA.MethodsThe FLT-1 gene polymorphisms were genotyped for 471 RA patients and 684 healthy individuals. Correlation analysis was performed with clinical parameters, cardiovascular disease (CVD) and anti-citrullinated peptide/protein antibody (ACPA) presence. The sFLT-1 serum levels were evaluated.ResultsThe FLT-1 gene polymorphisms showed no significant differences in the proportion of cases and controls. Furthermore, the FLT-1 rs2296188 T/C polymorphism was associated with ACPA-positive RA. Overall, rs9943922 T/C and rs2296283 G/A are in almost completed linkage disequilibrium (LD) with D’ = 0.97 and r2 = 0.83. The FLT-1 rs7324510 A allele has shown association with VAS score (p = 0.035), DAS-28 score (p = 0.013) and ExRA presence (p = 0.027). Moreover, other clinical parameters were also higher in RA patients with this allele. In addition, FLT-1 genetic variants conferred higher sFLT-1 levels in RA patients compared to controls.ConclusionFLT-1 rs7324510 C/A variant may be a new genetic risk factor for severity of RA. Examined factor highly predispose to more severe disease activity as well as higher sFLT-1 levels in RA.

Physical workload is associated with increased risk of rheumatoid arthritis: results from a Swedish population-based case–control study

ObjectivesThis study investigated: (1) the association of physical workload (PW) and risk of rheumatoid arthritis (RA); (2) the potential interactions between PW and the genes in the human leucocyte antigen...

A genetic risk score composed of rheumatoid arthritis risk alleles, HLA-DRB1 haplotypes, and response to TNFi therapy - results from a Swedish cohort study.

BackgroundTo prevent debilitating and irreversible joint damage, rheumatoid arthritis (RA) is often treated with tumor necrosis factor inhibitor (TNFi), but many patients do not respond to this costly therapy. Few predictors for response are known, and it has been proposed that genetic factors which influence the development of RA may also influence disease severity and response to therapy. Several previous studies have attempted to confirm this but results remain inconclusive. We expand on previous studies by including more RA risk alleles, and maximize power by combining them into a genetic risk score.MethodWe linked genotyped RA patients from the Epidemiological Investigation of Rheumatoid Arthritis study to the Swedish Rheumatology Quality Register, identifying patients who started a TNFi as their first biological disease-modifying anti-rheumatic drug, with a return visit within 2–8 months after treatment start (N = 867). We calculated risk scores from 76 established RA risk SNPs, and four HLA-DRB1 amino acid positions, and tested whether risk scores or individual genetic risk factors could predict the European League Against Rheumatism (EULAR) response.ResultsWe found no association between any of the risk scores or HLA-DRB1 haplotypes and EULAR response, neither overall nor stratified by anti-citrullinated protein/peptide antibody (ACPA) status. When evaluating each of the 76 SNPs, we found that the number of SNPs presenting significant associations was not higher than expected by chance (5/76 SNPs had p < 0.05 in ACPA-positive RA, 4/76 in ACPA-negative RA).ConclusionOverall, known RA risk SNPs do not predict response to TNFi, either individually or when combined into a risk score. This does not support the hypothesis that genes influencing RA onset would also influence its prognosis and treatment response.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1174-z) contains supplementary material, which is available to authorized users.

High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis.

BackgroundTwin studies are powerful models to elucidate epigenetic modifications resulting from gene–environment interactions. Yet, commonly a limited number of clinical twin samples are available, leading to an underpowered situation afflicted with false positives and hampered by low sensitivity. We investigated genome-wide DNA methylation data from two small sets of monozygotic twins representing different phases during the progression of rheumatoid arthritis (RA) to find novel genes for further research.MethodsWe implemented a robust statistical methodology aimed at investigating a small number of samples to identify differential methylation utilizing the comprehensive CHARM platform with whole blood cell DNA from two sets of twin pairs discordant either for ACPA (antibodies to citrullinated protein antigens)-positive RA versus ACPA-negative healthy or for ACPA-positive healthy (a pre-RA stage) versus ACPA-negative healthy. To deconvolute cell type-dependent differential methylation, we assayed the methylation patterns of sorted cells and used computational algorithms to resolve the relative contributions of different cell types and used them as covariates.ResultsTo identify methylation biomarkers, five healthy twin pairs discordant for ACPAs were profiled, revealing a single differentially methylated region (DMR). Seven twin pairs discordant for ACPA-positive RA revealed six significant DMRs. After deconvolution of cell type proportions, profiling of the healthy ACPA discordant twin-set revealed 17 genome-wide significant DMRs. When methylation profiles of ACPA-positive RA twin pairs were adjusted for cell type, the analysis disclosed one significant DMR, associated with the EXOSC1 gene. Additionally, the results from our methodology suggest a temporal connection of the protocadherine beta-14 gene to ACPA-positivity with clinical RA.ConclusionsOur biostatistical methodology, optimized for a low-sample twin design, revealed non-genetically linked genes associated with two distinct phases of RA. Functional evidence is still lacking but the results reinforce further study of epigenetic modifications influencing the progression of RA. Our study design and methodology may prove generally useful in twin studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0374-0) contains supplementary material, which is available to authorized users.