Anti-citrullinated Protein Antibodies Negative Rheumatoid Arthritis Research Articles

How RA Associated HLA-DR Molecules Contribute to the Development of Antibodies to Citrullinated Proteins: The Hapten Carrier Model.

The risk to develop ACPA positive rheumatoid arthritis (RA), the most destructive type of autoimmune arthritis, is carried by HLA-DRB1 alleles containing a 5 amino acid motif: the shared epitope (SE). RA is preceded by the emergence of disease specific anti citrullinated protein antibodies (ACPA). SE positive HLA-DRB1 alleles are associated with ACPA and ACPA positive RA, not with ACPA negative RA, suggesting that ACPA contribute to the pathogenesis of RA. Understanding how HLA-DRB1 genotypes influence ACPA could lead to a curative or preventive treatment of RA. The “Shared epitope binds citrullinated peptides “ hypothesis suggests that RA associated HLA-DR alleles present citrullinated peptides to T cells that help ACPA producing B cells. The “Hapten carrier model” suggests that PAD4 is the target of the T cells which help ACPA specific B cells through a hapten carrier mechanism in which PAD4 is the carrier and citrullinated peptides are the haptens. Direct binding assay of citrullinated peptides to purified HLA-DR molecules does not support the “shared epitope binds citrullinated peptides” hypothesis. The Odds Ratios to develop ACPA positive RA associated with each of 12 common HLA-DRB1 genotypes match the probability that the two HLA-DR molecules they encode can bind at least one peptide from PAD4, not from citrullinated fibrinogen. Thus, PAD4 tolerization might stop the carrier effect and switch off production of ACPA.

Effectiveness of four dynamic treatment strategies in patients with anticitrullinated protein antibody-negative rheumatoid arthritis: a randomised trial

ObjectiveTo determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis.MethodsIn the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2)...

Meta-Analysis of the Association of HLA-DRB1 with Anti-Citrullinated Protein Antibody-Positive and Anti-Citrullinated Protein Antibody-Negative Rheumatoid Arthritis

Because of genetic complex and variations of auto antibodies of rheumatoid arthritis (RA) in different populations, the data on the association of HLA-DRB1 alleles in anti-citrullinated protein antibody of (ACPA) RA were inconsistent. The purpose of the study is to systematically summarize results of published data through performing a meta-analysis using data in which HLA-DRB1 alleles are associated with ACPApositive RA and ACPA-negative RA. In this study, we collected data from 12 studies with 13,861 cases and 12,896 controls. Information in these studies included HLADRB1 typing and ACPA status from different countries. Odds ratios (ORs) and corresponding 95% confidence intervals (CI) were used to analyze the association of different HLA-DRB1 alleles with ACPA-positive RA or ACPA-negative RA. To correct skewing data, the analysis of ACPA-status was stratified by patient distribution. Our analyses indicate that in ACPA-positive RA, all patients with RA had significantly higher frequencies of HLA-DRB1*01, *04, *0401, *0405, *07, *11, *13 and *14 than controls. One of the HLA-DRB1*07, *11, *13 and *14 showed protective association with RA. In addition, HLA-DRB1*03, *10 and *12 had more influence than control to RA in European populations; the HLA-DRB1*03 and *12 alleles were associated with the protection. In ACPA-negative RA, only DRB1*07 was associated with the protection (OR 0.53 [95% CI 0.36 - 0.76]) among all HLA-DRB1 alleles in European populations. In ACPA-positive RA, currently available results indicate that *01, *04, *0401 and *0405 are susceptible, while HLA-DRB1*07, *11, *13 and *14 are protective in all populations. While the HLA-DRB1*10 is susceptible, HLA-DRB1*03 and *12 show protective association with RA in European populations. Additionally, regardless of the positive or negative ACPA, the DRB1*07 is always associated with protection in European populations.

AB0167 Autocitrullinated peptidylarginine deiminase from porphyromonas gingivalis part of an infection model in RA?

BackgroundBacteria release outer membrane vesicles (OMV) which do contain proteins, DNA and enzymes like Peptidylarginine Deiminase from Porphyromonas gingivalis (PPAD) to interact with bacteria and the host immune system. PPAD...

Association between body mass index and anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis: Results from a population‐based case–control study

Being overweight or obese is associated with many chronic diseases, but previous studies of the association with rheumatoid arthritis (RA) have shown inconsistent results. The aim of this study was to investigate the association between body mass index (BMI) and the risk of developing the 2 main subtypes of RA. At inclusion, cases and controls answered questions about their weight and height and donated blood samples. The presence of antibodies to citrullinated protein antigens (ACPAs) was analyzed among 2,748 cases and 3,444 controls (28% men). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using conditional logistic regression. Compared to those with normal weight (BMI <25 kg/m(2) ), the adjusted overall OR for developing ACPA-negative RA was 1.1 (95% CI 0.9-1.3) for overweight individuals (BMI ≥25 to <30 kg/m(2) ) and 1.4 (95% CI 1.1-1.9) for obese individuals (BMI ≥30 kg/m(2) ). When stratified by sex, the OR for ACPA-negative RA for obese women was 1.6 (95% CI 1.2-2.2), and there was no association between obesity and ACPA-negative RA in men (OR 1.1, 95% CI 0.6-1.8). In obese men compared to men with normal weight, the OR for ACPA-positive RA was 0.6 (95% CI 0.3-0.9), while there was no association between BMI and ACPA-positive RA among women (OR 1.0, 95% CI 0.8-1.2). Our findings show that obesity is associated with developing ACPA-negative RA in women, and indicate an inverse association between BMI and ACPA-positive RA in men.

Presence of Multiple Independent Effects in Risk Loci of Common Complex Human Diseases

Many genetic loci and SNPs associated with many common complex human diseases and traits are now identified. The total genetic variance explained by these loci for a trait or disease, however, has often been very small. Much of the "missing heritability" has been revealed to be hidden in the genome among the large number of variants with small effects. Several recent studies have reported the presence of multiple independent SNPs and genetic heterogeneity in trait-associated loci. It is therefore reasonable to speculate that such a phenomenon could be common among loci known to be associated with a complex trait or disease. For testing this hypothesis, a total of 117 loci known to be associated with rheumatoid arthritis (RA), Crohn disease (CD), type 1 diabetes (T1D), or type 2 diabetes (T2D) were selected. The presence of multiple independent effects was assessed in the case-control samples genotyped by the Wellcome Trust Case Control Consortium study and imputed with SNP genotype information from the HapMap Project and the 1000 Genomes Project. Eleven loci with evidence of multiple independent effects were identified in the study, and the number was expected to increase at larger sample sizes and improved statistical power. The variance explained by the multiple effects in a locus was much higher than the variance explained by the single reported SNP effect. The results thus significantly improve our understanding of the allelic structure of these individual disease-associated loci, as well as our knowledge of the general genetic mechanisms of common complex traits and diseases.

Variants Within STAT Genes Reveal Association with Anticitrullinated Protein Antibody-negative Rheumatoid Arthritis in 2 European Populations

STAT3 and 4 are, among other factors, critical for the interleukin 12 (IL-12)-mediated Th1 response, for transfer of IL-23 signals, and for survival and expansion of Th17 cells. We investigated the association of STAT3 and STAT4 polymorphisms with serologically distinct subgroups of rheumatoid arthritis (RA). A total of 41 single-nucleotide polymorphisms (SNP) within STAT3 and STAT1-STAT4 loci were investigated in a Swedish cohort of 2043 RA cases and 1115 controls. Nine of the associated SNP were tested in a Spanish cohort of 1223 RA cases and 1090 controls. Fourteen SNP in the STAT3 and STAT1-STAT4 loci were associated with anticitrullinated protein antibody (ACPA)-negative RA in the Swedish cohort. Three of the SNP in STAT4 and 2 SNP in STAT3 remained associated with ACPA-negative RA after considering the Spanish results. In addition, rs7574865 and rs10181656, in STAT4, were associated with ACPA-positive RA in the Swedish study. One of these SNP, rs7574865, showed a similar pattern of the association in serologically distinct subgroups of RA in a metaanalysis of all 7 published studies. Our findings suggest that variants in STAT genes may contribute differentially to susceptibility to RA in seropositive and in seronegative patients.

Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study)

AimClassifying more patients as rheumatoid arthritis (RA) (2010 American College of Rheumatology/European League Against Rheumatism criteria for RA) may improve treatment outcomes but may cause overtreatment in daily practice. The...

Associations of HLA-DRB1 alleles with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in northern east part of Turkey

The aim of this study was to investigate the associations between human leukocyte antigen (HLA)-DRB1 alleles with genetic susceptibility to rheumatoid arthritis (RA) and production of antibodies against cyclic citrullinated peptide (anti-CCP antibody) and rheumatoid factor (RF) in Turkish RA patients. We studied 291 RA patients and 253 controls. Genotyping was performed by polymerase chain reaction with sequence-specific oligonucleotide probes hybridization method. Serum levels of anti-CCP antibody, IgM-RF and high sensitive C-reactive protein titers were measured by commercial kits using immunological methods. We found that HLA-DRB1*04 and *09 alleles were associated in anti-CCP+ and anti-CCP+ RA patients (P < 0.0001 and P < 0.001, respectively), while DRB1*01 and *04 were determined to be higher in RF+ RA patients (P < 0.001 and P < 0.0001, respectively). Moreover, DRB1*11 and DRB1*13 alleles were determined to be lower in RF and anti-CCP/RF+ RA patients (P < 0.001 for both). HLA-DRB1*04 was identified as a common responsible allele for susceptibility to the disease in anti-CCP, RF and anti-CCP/RF- RA patients (P = 0.0018, P = 0.0004 and P = 0.0023, respectively). HLA-DRB1*13 allele alone was found to be protective against to anti-CCP+ and RF- RA (P = 0.0003 and P = 0.006, respectively). On the contrary, there was no protective allele in anti-CCP/RF- RA as well as anti-CCP- RA patients. This study indicates that associate and protective HLA-DRB1 allele distributions are different in autoantibody (anti-CCP or RF or anti-CCP/RF)+ RA and autoantibody- RA patients, with exceptions of DRB1*04 and DRB1*13.

The rheumatoid arthritis HLA–DRB1 shared epitope

To update progress made between December 2008 and November 2009 on the role of the rheumatoid arthritis (RA)-shared epitope in the cause and pathogenesis of RA. New evidence has been recently presented to suggest that noninherited human leukocyte antigens (HLAs) originating through pregnancy or exposure to maternal antigens in utero could contribute to RA development in shared epitope-negative women. An interaction between smoking and shared epitope-coding non-*04 HLA-DRB1 alleles (particularly HLA-DRB1*01 and HLA-DRB1*10) was formally established for the first time. Progress has been made in determining the relative contributions and the interaction of the shared epitope, PTPN22 and smoking in conferring the risk of anticitrullinated protein antibodies-positive and negative RA. The autoantigen that anticitrullinated protein antibodies recognize in a significant number of RA patients has been identified as citrullinated alpha-enolase and the importance of genetic factors in anticitrullinated protein antibodies-negative RA has been highlighted. Additionally, associations of RA risk with several new genetic markers have been reported. Among them: two new major histocompatibility complex, non-DRB1 loci, a polymorphism marker in major histocompatibility complex class I polypeptide-related sequence A, an allele of the Fcgamma receptor, a polymorphism marker in the beta2-adrenergic receptor and a low-inducible allele of the cytochrome P450 subtype 1A2. Although the mechanistic basis of shared epitope-RA association remains an enigma, observations made during the last year shed new light on the conditions in which the shared epitope - alone or in combination with other genes or environmental factors - affects the risk of RA and the phenotype of the disease.

Protection against anti–citrullinated protein antibody–positive rheumatoid arthritis is predominantly associated with HLA–DRB1*1301: A meta‐analysis of HLA–DRB1 associations with anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis in four European populations

The protective effect of HLA-DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA-DRB1 alleles are associated with protection in anti-citrullinated protein antibody (ACPA)-positive RA and ACPA-negative RA. Data for >2,800 patients and >3,000 control subjects for whom information on HLA-DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA-DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association. In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA-DRB1*13 alleles (OR 0.54 [95% CI 0.38-0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75-1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09-0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA-DRB1 alleles. Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA-DRB1*1301.

Opposing effects of HLA–DRB1*13 alleles on the risk of developing anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

The effect of non-shared epitope HLA-DRB1 alleles on rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate the effects of several HLA-DRB1 alleles, independent of the shared epitope, on the risk of developing anti-citrullinated protein antibody (ACPA)-positive or ACPA-negative RA in a large case-control study. HLA typing for the DRB1 gene was performed in 1,352 patients with RA and 922 controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated. DRB1*13 was found to protect against ACPA-positive RA when stratifying for the shared epitope and using a dominant genetic model (RR 0.41 [95% CI 0.26-0.64]). Furthermore, DRB1*13 neutralized the effect of the shared epitope in ACPA-positive RA (RR 3.91 [95% CI 3.04-5.02] in patients who had the shared epitope but not DRB1*13, and RR 1.22 [95% CI 0.81-1.83] in patients with both the shared epitope and DRB1*13, as compared with patients negative for both the shared epitope and DRB1*13). However, we did not replicate the previous published risk of ACPA-negative RA conferred by DRB1*03 when a dominant genetic model was used (RR 1.29 [95% CI 0.91-1.82]). Similarly, no significant effect of DRB1*03 on RR for ACPA-negative RA was seen using the recessive genetic model (RR 1.18 [95% CI 0.6-2.4]). In contrast, the combination of DRB1*03 and DRB1*13 was significantly associated with increased risk of developing ACPA-negative RA (RR 2.07 [95% CI 1.17-3.67]). Our findings indicate that the DRB1*13 allele plays a dual role in the development of RA, by protecting against ACPA-positive RA but, in combination with DRB1*03, increasing the risk of ACPA-negative RA.

Quantitative heritability of anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with anti-citrullinated protein antibody (ACPA)-positive RA, while far fewer genetic risk factors have been identified for ACPA-negative RA. This study was undertaken to quantify the contribution of genetic risk factors in general, and of the predisposing HLA-DRB1 shared epitope (SE) alleles in particular, to the ACPA-positive and ACPA-negative subsets of RA, by computing their heritability and assessing the contribution of the HLA SE alleles. One hundred forty-eight RA twin pairs, in which at least 1 twin of each pair had RA, were tested for ACPAs and typed for HLA-DRB1 genotypes. Heritability was assessed in a logistic regression model including a bivariate, normally distributed random effect, representing the contribution of unobserved genetic factors to RA susceptibility, with the correlation of the random effects fixed according to twin zygosity. The contribution of the HLA SE alleles to genetic variance was assessed using a similar model, except that estimates were based on genotype-specific population prevalences. The heritability of RA among the twin pairs was 66% (95% confidence interval [95% CI] 44-75%). For ACPA-positive RA, the heritability was 68% (95% CI 55-79%), and for ACPA-negative RA it was 66% (95% CI 21-82%). Presence of the HLA SE alleles explained 18% (95% CI 16-19%) of the genetic variance of ACPA-positive RA but only 2.4% (95% CI 1.6-10%) of the genetic variance of ACPA-negative RA. The heritability of ACPA-positive RA is comparable with that of ACPA-negative RA. These data indicate that genetic predisposition plays an important role in the pathogenesis of ACPA-negative RA, for which most individual genetic risk factors remain to be identified.

Different patterns of associations with anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis in the extended major histocompatibility complex region

To identify additional variants in the major histocompatibility complex (MHC) region that independently contribute to risk in 2 disease subsets of rheumatoid arthritis (RA) defined according to the presence or absence of antibodies to citrullinated protein antigens (ACPAs). In a multistep analytical strategy using unmatched as well as matched analyses to adjust for HLA-DRB1 genotype, we analyzed 2,221 single-nucleotide polymorphisms (SNPs) spanning 10.7 Mb, from 6p22.2 to 6p21.31, across the MHC. For ACPA-positive RA, we analyzed samples from the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) and the North American Rheumatoid Arthritis Consortium (NARAC) studies (totaling 1,255 cases and 1,719 controls). For ACPA-negative RA, we used samples from the EIRA study (640 cases and 670 controls). Plink and SAS statistical packages were used to conduct all statistical analyses. A total of 299 SNPs reached locus-wide significance (P<2.3x10(-5)) for ACPA-positive RA, whereas surprisingly, no SNPs reached this significance for ACPA-negative RA. For ACPA-positive RA, we adjusted for known DRB1 risk alleles and identified additional independent associations with SNPs near HLA-DPB1 (rs3117213; odds ratio 1.42 [95% confidence interval 1.17-1.73], Pcombined=0.0003 for the strongest association). There are distinct genetic patterns of MHC associations in the 2 disease subsets of RA defined according to ACPA status. HLA-DPB1 is an independent risk locus for ACPA-positive RA. We did not identify any associations with SNPs within the MHC for ACPA-negative RA.