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1.  The Influence of Polygenic Risk Scores on Heritability of Anti-CCP Level in RA 
Genes and immunity  2014;15(2):107-114.
Objective
To study genetic factors that influence quantitative anti-cyclic citrullinated peptide (anti-CCP) antibody levels in RA patients.
Methods
We carried out a genome wide association study (GWAS) meta-analysis using 1,975 anti-CCP+ RA patients from 3 large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC), and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels.
Results
GWAS-meta analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a p-value of 2×10−11 for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5×10−8, and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r2 in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a p-value of 3×10−7. None of the known RA risk alleles (~52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants.
Conclusions
Anti-CCP level is a heritable trait. HLA-DR3 and GP2 are associated with lower anti-CCP levels.
doi:10.1038/gene.2013.68
PMCID: PMC3948067  PMID: 24385024
RA; GWAS; anti-CCP; heritability
2.  Genome-Wide Association Study of Determinants of Anti-Cyclic Citrullinated Peptide Antibody Titer in Adults with Rheumatoid Arthritis 
Molecular Medicine  2009;15(5-6):136-143.
We carried out a genome-wide association study of genetic predictors of anti-cyclic citrullinated peptide antibody (anti-CCP) level in 531 self-reported non-Hispanic Caucasian Rheumatoid Arthritis (RA) patients enrolled in the Brigham Rheumatoid Arthritis Sequential Study (BRASS). For replication, we then analyzed 289 single nucleotide polymorphisms (SNPs) with P < 0.001 in BRASS in an independent population of 849 RA patients from the North American Rheumatoid Arthritis Consortium (NARAC). BRASS and NARAC samples were genotyped using the Affymetrix 100K and Illumina 550K platforms respectively. Association between SNPs and anti-CCP titer was tested using general linear models. The five most significant SNPs from BRASS all were within the major histocompatibility complex (MHC) region (P ≤ 3.5 × 10−6). After controlling for the human leukocyte antigen shared epitope (HLA-SE), the top SNPs still yielded P values < 0.0002. In NARAC, a single SNP from the MHC region near BTNL2 and HLA-DRA, rs1980493 (r2 = 0.85 with the top five SNPs from BRASS), was associated significantly with CCP titer (P = 6.1 × 10−5) even after adjustment for the HLA-SE (P = 0.0002). The top SNPs found in BRASS and NARAC had r2 = 0.46 and 0.64, respectively, to HLA-DRB1 DR3 alleles. These results confirm that the most significant genome region affecting anti-CCP titers in RA is the MHC region. We identified a SNP in moderate linkage disequilibrium (LD) with HLA-DR3, which may influence anti-CCP titer independently of the HLA-SE.
doi:10.2119/molmed.2009.00008
PMCID: PMC2654848  PMID: 19287509
3.  Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset 
Arthritis Research  2000;2(3):236-243.
An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-SA identified a subset of predominantly male RA patients with severe, erosive disease. Anti-SA, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses.
Introduction:
A spectrum of autoantibodies is now known to be specifically associated with RA. There continues to be uncertainty as to what stage of the disease each of these autoantibodies develop, and whether they are associated with unique clinical features.
Aims:
To help address these questions, a spectrum of autoantibodies known to be associated with RA in a cohort of patients with early synovitis was evaluated.
Methods:
An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinicially then followed prospectively for 1 year. Patients were classified as having RA on the basis of fulfilling the 1987 criteria. Serum samples collected at the time of the initial evaluation were tested for anti-Sa and anti-RA-33 using immunoblotting, and to (pro)filaggrin (AFA), anti-CCP, and calpastatin (anti-RA-1) using enzyme-linked immunosorbent assay techniques. AKA were detected using immunoflurescence on human epidermal tissue. RF was tested by nephelometry. HLA-DRB1 alleles were determined using sequence specific primers. Initial and 1 year radiographs were evaluated for the presence of erosions.
Results:
Of the 238 patients with synovitis of recent onset in the cohort, 106 (45%) met RA criteria, 102 (96%) of whom met the criteria on their initial visit. Diagnoses in the remaining patients included 22 (9%) with reactive arthritis, 14 (6%) with psoriatic arthritis or another form of spondylarthropathy, 11 (5%) with another well-defined rheumatic diagnosis, and 85 (36%) with undifferentiated arthritis. The RA patients were significantly older than the nonRA patients (46 ± 13 versus 39 ± 13; P < 0.001), had higher mean swollen joint count (13.8 ± 9.7 versus 2.3 ± 2.3; P < 0.001), and higher C-reactive protein (CRP) level (1.9 ± 1.9 versus 1.6 ± 2.4; P < 0.01). Table 1 summarizes the prevalence of the various RA associated antibodies in patients diagnosed as having RF-positive (RF+) RA, RF-negative (RF-) RA, and nonRA. Regarding the characteristics of these tests, RF had the highest sensitivity at 66%, and all the other antibodies individually were less than 50% sensitive. AFA, anti-Sa, anti-CCP were greater than 90% specific for RA, while RF and AKA were 80-90% specific, and anti-RA-33 and anti-RA-1 was not specific for this diagnosis. The data further indicate that adding any one of AFA, AKA, anti-Sa, or anti-CCP to RF increases the specificity for RA from 80 to 90%. In the absence of RF, the presence of one or more of these antibodies carried a sensitivity of only 31% for RF- RA, with anti-Sa being the most specific at 98%. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Despite this high level of correlation, of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one, suggesting considerable variability in individual reactivity patterns.
RA has been shown in multiple populations to be associated with HLA-DRB1 alleles encoding for the shared epitope (SE). In this study, as illustrated in Table 2, the presence of each of these autoantibodies was significantly associated with having two shared epitope alleles, even when only the RA patients were considered.
Patients with anti-Sa antibodies were predominantly male (61% versus 28%; P<0.01), had significantly higher swollen joint counts (18 ± 12 versus 13 ± 9; P=0.02), and higher CRP levels (2.6 ± 3 mg/dl versus 1.6 ± 1.4 mg/dl; P=0.03) at the initial visit. Despite subsequently begin treated with significantly higher doses of prednisone (4.8 ± 6.0 mg/day versus 1.8 ± 3.3 mg/day; P<0.01), and more disease modifying antirheumatic drug therapy (1.4 ± 0.8 versus 0.9 ± 0.7 disease modifying antirheumatic drugs; P<0.01), the anti-Sa-positive RA patients had a higher frequency of erosions than the rest of the RA patients (60% versus 33%; P=0.03). Neither RF nor SE were associated with the disease severity measures, and analyses evaluating all the other autoantibodies failed to reveal a similar trend.
Discussion:
Despite a well-documented lack of specificity, RF continues to be a central part of the definition of RA, primarily because of its favourable sensitivity profile. In our cohort, RF had a sensitivity of 66%, a specificity of 87%, and an overall accuracy of 78% for the diagnosis of RA. AFA, anti-Sa, anti-CCP were all highly specific for this diagnosis, and when any of them were present in conjunction with RF, the specificity for RA approached 100%. Potentially of more importance to the clinician is the diagnostic value of these antibodies when RF is not detectable. Our data indicate that only 31% of RF- RA patients had any of AKA, AFA, anti-Sa or anti-CCP, and that anti-Sa was the most specific for this diagnosis. This modest level of sensitivity suggests that testing for this spectrum of autoantibodies carries little advantage over RF alone in diagnosing early RA.
AFA, AKA, and antiperinuclear factor (APF) have all been proposed to identify a common antigen present in the skin protein (pro)filaggrin. It has continued to be puzzling why a skin antigen would be targeted relatively specifically in a disorder that is primarily articular. A potential explanation for this may relate to the demonstration that citrulline appears to be an essential constituent of the antigenic determinants recognized by AKA, APF, and AFA. The citrulline rich (pro)filaggrin molecule makes an ideal substrate for detecting this reactivity. Moreover, the SA antigen, which, unlike (pro)filaggrin, is detectable in rheumatoid synovium, has recently been shown to also be citrullinated. It is thus possible that AKA, AFA, APE, and anti-Sa all recognize one or more citrullinated antigens. Despite this possibility, the modest degree of concordance between them in individual patient sera suggests that it is unlikely that a single antigen is involved in generating these responses.
This study provides evidence suggesting that anti-Sa antibodies appear to be a marker for a subset of early RA patients whose disease may be more severe and erosive. Moreover, it was determined that anti-Sa, AFA, and anti-CCP were all highly associated with SE, particularly two copies. We examined a spectrum of potential RA severity indicators including the number of swollen joints, CRP level, and presence of early radiographic erosions. Our data indicate that anti-Sa was more highly associated with these measures of RA severity than any other parameter, including the most accepted prognostic indicators, RF and SE.
In conclusion, it is demonstrated that antibodies directed against putatively citrullinated antigens including SA, filaggrin, keratin, and CCP are the most specific for RA, and are detectable early in the disease course. It will be of interest to find out whether the cumulative prevalence of specific autoantibody subsets tends to increase over time, as this would suggest that the mechanisms underlying the development of these reactivities continue to evolve over the course of the arthropathy.
PMCID: PMC17811  PMID: 11056669
autoantibodies; early synovitis; human leukocyte antigen; rheumatoid arthritis; spondylarthropathy
4.  Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project 
Introduction
The present study was carried out to assess whether IgA-class antibodies against cyclic citrullinated peptides (IgA anti-CCP) in recent-onset rheumatoid arthritis add diagnostic and/or prognostic information to IgG anti-CCP analysis.
Methods
Serum samples were obtained from 228 patients with recent-onset (<12 months) rheumatoid arthritis at the time of inclusion in the Swedish TIRA cohort (Swedish Early Intervention in Rheumatoid Arthritis). Sera from 72 of these patients were also available at the 3-year follow-up. Disease activity and functional ability measures (erythrocyte sedimentation rate, serum C-reactive protein, 28-joint count Disease Activity Score, physician's assessment of disease activity, and the Swedish version of the Health Assessment Questionnaire) were registered at inclusion and at regular follow-ups during 3 years. An IgA anti-CCP assay was developed based on the commercially available IgG-specific enzyme immunoassay from EuroDiagnostica (Arnhem, the Netherlands), replacing the detection antibody by an anti-human-IgA antibody. A positive IgA anti-CCP test was defined by the 99th percentile among healthy blood donors.
Results
At baseline, a positive IgA anti-CCP test was observed in 29% of the patient sera, all of which also tested positive for IgG anti-CCP at a higher average level than sera containing IgG anti-CCP alone. The IgA anti-CCP-positive patients had significantly higher disease activity over time compared with the IgA anti-CCP-negative patients. After considering the IgG anti-CCP level, the disease activity also tended to be higher in the IgA anti-CCP-positive cases – although this difference did not reach statistical significance. The proportion of IgA anti-CCP-positive patients was significantly larger among smokers than among nonsmokers.
Conclusion
Anti-CCP antibodies of the IgA class were found in about one-third of patients with recent-onset rheumatoid arthritis, all of whom also had IgG anti-CCP. The occurrence of IgA-class antibodies was associated with smoking, and IgA anti-CCP-positive patients had a more severe disease course over 3 years compared with IgA anti-CCP-negative cases. Although IgA anti-CCP analysis does not seem to offer any diagnostic information in addition to IgG anti-CCP analysis, further efforts are justified to investigate the prognostic implications.
doi:10.1186/ar2449
PMCID: PMC2575621  PMID: 18601717
5.  Relationship between Anti-CCP Antibodies and Oxidant and Anti-Oxidant Activity in Patients with Rheumatoid Arthritis 
Objective/Aim: A new group of autoantibodies in Rheumatoid Arthritis (RA), the anti-cyclic citrullinated peptide (anti-CCP) antibodies directed to citrulline-containing proteins, which are of value for the severity of RA. Up to date, the relationship between anti-CCP antibodies and oxidant, anti-oxidant activity in patients with RA has not been elucidated in the previous studies. In this study we aimed to investigate the effect of anti-CCP antibodies in the circulation on whole blood, serum and synovial fluid oxidant and anti-oxidant activity in patients with RA. Materials and Methods: RA patients with anti-CCP (+) (n=25) and anti-CCP (-) (n=24) were recruited into the study. All patients had a positive rheumatoid factor (RF). The patients who were under treatment with only non-steroidal antiinflammatory drugs (NSAID) at the study time included in the study. Catalase (CAT), Glutathione peroxidase (GSHPx), Myeloperoxidase (MPO) activities and the levels of Malondialdehyde (MDA) were measured in whole blood, serum and synovial fluid in both groups. Results: There were no significant differences in terms of the mean whole blood and serum antioxidative activity (CAT, GSHpx) and the mean blood and serum MDA and MPO values (oxidative activity), between the patients with anti-CCP(+) and those with anti-CCP(-). There was increased synovial oxidant activity (MDA and MPO levels) (p<0.05) in anti-CCP(+) RA patients with or without ESR negativity when compared with anti-CCP(-) RA patients. There was positive correlation between anti-CCP antibody levels and synovial MDA and MPO levels (r=0.435, p<0.05, r=0.563, p<0.05 respectively) in anti-CCP (+) group. Conclusions: In conclusion, anti-CCP antibody positivity seems to be associated with increased synovial fluid oxidant activity (increased MDA and MPO levels) in patients with RA. These conclusions need to be validated in a larger controlled study population.
PMCID: PMC3039229  PMID: 21326956
Oxidative stress; Rheumatoid arthritis; Anti-CCP antibody; Malondialdehyde; Myeloperoxidase; Synovial fluid
6.  TRAF1-C5 as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study 
The New England journal of medicine  2007;357(12):1199-1209.
BACKGROUND
Rheumatoid arthritis has a complex mode of inheritance. Although HLA-DRB1 and PTPN22 are well-established susceptibility loci, other genes that confer a modest level of risk have been identified recently. We carried out a genomewide association analysis to identify additional genetic loci associated with an increased risk of rheumatoid arthritis.
METHODS
We genotyped 317,503 single-nucleotide polymorphisms (SNPs) in a combined case-control study of 1522 case subjects with rheumatoid arthritis and 1850 matched control subjects. The patients were seropositive for autoantibodies against cyclic citrullinated peptide (CCP). We obtained samples from two data sets, the North American Rheumatoid Arthritis Consortium (NARAC) and the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA). Results from NARAC and EIRA for 297,086 SNPs that passed quality-control filters were combined with the use of Cochran-Mantel-Haenszel stratified analysis. SNPs showing a significant association with disease (P<1×10-8) were genotyped in an independent set of case subjects with anti-CCP-positive rheumatoid arthritis (485 from NARAC and 512 from EIRA) and in control subjects (1282 from NARAC and 495 from EIRA).
RESULTS
We observed associations between disease and variants in the major-histocompatibility-complex locus, in PTPN22, and in a SNP (rs3761847) on chromosome 9 for all samples tested, the latter with an odds ratio of 1.32 (95% confidence interval, 1.23 to 1.42; P = 4×10-14). The SNP is in linkage disequilibrium with two genes relevant to chronic inflammation: TRAF1 (encoding tumor necrosis factor receptor-associated factor 1) and C5 (encoding complement component 5).
CONCLUSIONS
A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.
doi:10.1056/NEJMoa073491
PMCID: PMC2636867  PMID: 17804836
7.  Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis 
Annals of the Rheumatic Diseases  2005;64(8):1145-1149.
Background: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are considered highly specific markers of rheumatoid arthritis. Despite the high specificity of the test, anti-CCP antibodies have also been observed in psoriatic arthritis.
Objective: To determine the frequency of anti-CCP antibodies in psoriatic arthritis and to describe the clinical characteristics of such patients.
Methods: Serum samples from 192 patients with psoriatic arthritis were analysed for anti-CCP antibodies. A previously defined cut off point was applied at a specificity level of ⩾98.5% (42 U/ml). Antibodies against pepA and pepB (two synthetic citrullinated peptides) were determined on samples containing anti-CCP antibodies by line immune assay. The swollen joint count and the numbers of affected joints (present or past) were recorded. Clinical features were noted and if available radiographs of hands and feet were scored for erosions. Rheumatoid factor was determined in all samples.
Results: Anti-CCP antibodies were found in 15 patients (7.8%); 13 of 15 anti-CCP2 positive samples were also positive for anti-pepA or pepB antibodies. The prevalence of anti-CCP antibodies was higher than expected in view of the highly specific cut off applied in the test. Detailed analysis of the clinical and radiological features makes it improbable that the high prevalence of anti-CCP antibodies resulted solely from concomitant psoriasis and rheumatoid arthritis or from misclassification.
Conclusions: Anti-CCP antibodies may be present in patients with psoriatic arthritis. Although some of the present cohort could have had psoriasis with concomitant rheumatoid arthritis, a proportion at least had the typical characteristics of psoriatic arthritis as the primary diagnosis.
doi:10.1136/ard.2004.032177
PMCID: PMC1755603  PMID: 15695535
8.  Patients With Pulmonary Tuberculosis Are Frequently Positive for Anti–Cyclic Citrullinated Peptide Antibodies, but Their Sera Also React With Unmodified Arginine-Containing Peptide 
Arthritis and rheumatism  2008;58(6):1576-1581.
Objective
The anti–cyclic citrullinated peptide (anti-CCP) enzyme-linked immunosorbent assay (ELISA) has high sensitivity and specificity for rheumatoid arthritis (RA). However, detection of anti-CCP in patients with active pulmonary tuberculosis (TB) has recently been reported. To determine whether this activity was specific for the citrullinated residue, the specificity of anti-CCP–positive sera for CCP versus that for unmodified arginine-containing peptide (CAP) was examined in patients with TB and compared with that in patients with RA.
Methods
Anti-CCP and anti-CAP in sera from patients with pulmonary TB (n = 49), RA patients (n = 36), and controls (n = 18) were tested by ELISA. Sera were available at diagnosis from most TB patients. All TB patients were treated with a combination of 2–4 antibiotics for at least 6 months, and sera were collected over time.
Results
Anti-CCP was found in 37% of TB patients and in 43% of RA patients. CAP reactivity was more common in TB than in RA. High anti-CCP:anti-CAP ratios (>2.0) were seen far more commonly in anti-CCP–positive RA patients than in anti-CCP–positive TB patients (94% versus 22%). Anti-CCP was inhibited by CCP peptide in sera from RA patients, but not in sera from TB patients. A slight increase in anti-CCP was common after initiating treatment for TB, although the anti-CCP level decreased after 1–2 months.
Conclusion
Anti-CCP is frequently present in patients with active TB. However, many anti-CCP–positive TB sera also reacted with CAP, and anti-CCP: anti-CAP ratios in TB sera were low. Anti-CCP:anti-CAP ratios should be useful clinically for distinguishing CCP-specific reactivity seen in RA from reactivity with both CCP and CAP frequently seen in pulmonary TB.
doi:10.1002/art.23514
PMCID: PMC3621955  PMID: 18512773
9.  Citrulline Dependence of Anti-Cyclic Citrullinated Peptide Antibodies in Systemic Lupus Erythematosus as a Marker of Deforming/Erosive Arthritis 
The Journal of rheumatology  2009;36(12):2682-2690.
Objective
Anti-cyclic citrullinated peptide (CCP) antibodies are a serological marker for rheumatoid arthritis (RA); up to 10%–15% of patients with systemic lupus erythematosus (SLE) are also positive. While anti-CCP in RA is citrulline-dependent, anti-CCP in some other diseases is citrulline-independent and reacts with both CCP and the unmodified (arginine-containing) cyclic arginine peptide (CAP). We investigated the citrulline dependence of anti-CCP and its significance in the arthritis of SLE.
Methods
IgG anti-CCP was compared by ELISA to anti-CAP in sera from patients with SLE (n = 335) and RA (n = 47) and healthy controls (n = 35). SLE patients were divided into 5 groups based on their joint involvement: subset I: deforming/erosive arthritis (n = 20); II: arthritis fulfilling (or likely fulfilling) American College of Rheumatology criteria for RA but without erosions (n = 18); III: joint swelling but not fulfilling RA criteria (n = 39); IV: arthritis without documented joint swelling (n = 194); and V: no arthritis (n = 58).
Results
Anti-CCP (> 1.7 units) was found in 68% (32/47) of patients with RA and 17% (55/329) of those with SLE. It was more common in SLE patients with deforming/erosive arthritis (38%). High anti-CCP (> 10 units) was found in RA (26%) and deforming/erosive SLE (12%). High anti-CCP/CAP ratios (> 2, indicating a selectivity to CCP) were found in 91% of anti-CCP-positive RA and 50% of anti-CCP-positive SLE patients with deforming/erosive arthritis. Patients from subset II did not have high anti-CCP/CAP.
Conclusion
Citrulline dependence or high levels (> 10) of anti-CCP were common in SLE patients with deforming/erosive arthritis, while most anti-CCP in SLE patients was citrulline-independent. This may be useful in identifying a subset of SLE patients with high risk for development of deforming/erosive arthritis.
doi:10.3899/jrheum.090338
PMCID: PMC2803319  PMID: 19884269
ANTI-CYCLIC CITRULLINATED PEPTIDE ANTIBODY; RHEUMATOID ARTHRITIS; SYSTEMIC LUPUS ERYTHEMATOSUS; DEFORMING ARTHRITIS; CITRULLINATION
10.  Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint 
Arthritis Research & Therapy  2014;16(4):R167.
Introduction
A major subset of patients with rheumatoid arthritis (RA) is characterized by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPAs). These autoantibodies, which are commonly detected by using an enzyme-linked immunosorbent assay (ELISA) based on synthetic cyclic citrullinated peptides (CCPs), predict clinical onset and a destructive disease course. In the present study, we have used plasma and synovial fluids from patients with RA, for the affinity purification and characterization of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be used in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPAs that bind to autoantigens expressed in vivo in the major inflammatory lesions of RA (that is, in the rheumatoid joint).
Methods
Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels of above 300 AU/mL. Total IgG was isolated on Protein G columns and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analyzed for reactivity and specificity by using the CCPlus® ELISA, in-house peptide ELISAs, Western blot, and immunohisto-/immunocytochemistry.
Results
Approximately 2% of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from α-enolase, vimentin, fibrinogen, and collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but, more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from patients with RA.
Conclusions
We have isolated ACPAs from plasma and synovial fluid and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISAs, de facto act as surrogate antigens for at least four different, well-characterized, largely non-cross-reactive, ACPA fine specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPAs can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs.
doi:10.1186/ar4683
PMCID: PMC4448322  PMID: 25112157
11.  Adjusting for sex and anti-CCP levels in linkage analysis of rheumatoid arthritis 
BMC Proceedings  2007;1(Suppl 1):S75.
We incorporate population effects of sex and antibodies directed against cyclic citrullinated peptides (anti-CCP) into the linkage analysis of rheumatoid arthritis (RA) with microsatellites data provided by the North American Rheumatoid Arthritis Consortium in Genetic Analysis Workshop 15.
The method stems from a generalized linear mixed model that incorporates the marginal population effects of important covariates. The resulting test for linkage is based on a score test in a pseudo-likelihood of this model. The mathematical derivation is given elsewhere but the test has a simple and appealing form: it assigns weights to excess identity-by-descent sharing between pairs of related individuals depending on the individual-specific values of the covariates and phenotypes.
Although RA is three times more prevalent in women than in men, the weights derived for male-male, female-male, and female-female affected sib pairs turn out to be very similar and the sex-adjusted analysis hardly differs from an unadjusted analysis. High anti-CCP levels are known to strongly predict RA. Our test assigns very small weights to pairs whose anti-CCP levels are high for the two siblings, sib pairs with two low anti-CCP levels are those most contributing to the evidence for linkage. Comparison of the unadjusted and the anti-CCP-adjusted analyses identifies persisting peaks mapping to regions that can be attributed to a 'dimension' of RA independent of anti-CCP.
PMCID: PMC2367574  PMID: 18466577
12.  A genome-wide ordered-subset linkage analysis for rheumatoid arthritis 
BMC Proceedings  2007;1(Suppl 1):S101.
Rheumatoid arthritis (RA) is a chronic, complex autoimmune inflammatory disorder with poorly known etiology. Approximately 1% of the adult population is afflicted with RA. Linkage analysis of RA can be complicated by the presence of phenotypic and genetic heterogeneity. It is shown that the ordered-subset analysis (OSA) technique reduces heterogeneity, increases statistical power for detecting linkage and helps to define the most informative data set for follow-up analysis. We applied OSA to the family data from the North American Rheumatoid Arthritis Consortium study as part of the Genetic Analysis Workshop 15 (GAW15). We have incorporated two continuous covariates, 'age of onset' and 'anti-CCP level' (anti-cyclic citrinullated peptide), into our genome-wide ordered-subset linkage analysis using 809 Illumina SNP markers in 5713 individuals from 606 Caucasian RA families. A statistically significant increase in nonparametric linkage (NPL) scores was observed with covariate 'age of onset' in chromosomes 4 (p = 0.000003) and 9 (p = 0.002). With the covariate 'anti-CCP level', statistically significant increases in NPL scores were observed in chromosomes 2 (p = 0.0001), 18 (p = 0.00007), and 19 (p = 0.0003). Once we identified the linked genomic region, we then attempted to identify the best plausible parametric model at that linked locus. Our results show significant improvement in evidence for linkage and demonstrate that OSA is a useful technique to detect linkage under heterogeneity.
PMCID: PMC2367502  PMID: 18466441
13.  Unique Correlation Between Mutated Citrullinated Vimentine IgG Autoantibodies and Markers of Systemic Inflammation in Rheumatoid Arthritis Patients 
Rheumatoid arthritis (RA) is the most common inflammatory systemic autoimmune disease, primarily affecting the peripheral joints. Anti-mutated citrullinated vimentin autoantibodies (anti-MCV) of IgG isotype were shown to be a useful diagnostic marker of RA especially in RA patients who were anti-cyclic citrullinated protein autoantibodies (anti-CCP) negative. Nevertheless, published data correlates rheumatoid factor (RF), anti-CCP or anti-MCV antibodies with either erythrocyte sedimentation rate (ESR) or serum C-reactive protein (CRP) as markers of disease activity, not investigated the possible correlations of RA autoantibodies towards ESR and CRP in comparison. Herein, we aim to evaluate the usefulness of anti-MCV as a dependable marker in established RA compared with anti-CCP and RF antibodies and to examine correlations between RF, anti-CCP and anti-MCV antibodies towards ESR and serum CRP. Serum RF-IgA, RF-IgM, anti-CCP and anti-MCV levels were measured in 30 patients with RA and 40 patients with other autoimmune diseases (non-RA) compared with 20 normal subjects. Specificity, sensitivity and AUC for RF antibodies, anti-CCP and anti-MCV were calculated towards RA diagnosis. Our results showed that ESR and CRP had significantly higher values in both RA and non-RA patients compared with our healthy controls with observed significant increment in RA patients compared with non-RA patients. An important finding from our study is that 33.3 % of RA patients were anti-CCP negative but being positive towards anti-MCV. Also, in-between 36.7 up to 40 % of RA patients were RF-IgA and RF-IgM negative while being anti-MCV positive. Anti-MCV antibodies showed the highest specificity and sensitivity (97.5 and 86.6 %, respectively) towards RA diagnosis with the highest AUC value (0.920) compared with anti-CCP and RF antibodies. Correlation analyses revealed that there was no significant correlation between ESR along with CRP towards RF-IgA, RF-IgM and anti-CCP while profound highly significant correlation exhibited between ESR and CRP towards anti-MCV data (r = 0.879 and 0.994, respectively). Thus, our data suggest that the assessment of serum anti-MCV autoantibodies along with ESR and CRP considered as a simple laboratory regime for monitoring RA patients to assess and follow-up disease activity. The addition of anti-MCV autoantibodies to serologic markers in the ACR/EULAR classification criteria for RA will add points for patients with negative anti-CCP and RF antibodies.
doi:10.1007/s12291-012-0272-1
PMCID: PMC3689334  PMID: 24426223
Rheumatoid arthritis; Anti-mutated citrullinated vimentine antibodies; Specificity; Sensitivity; C-reactive protein; Erythrocyte sedimentation rate
14.  Anti-cyclic citrullinated peptide antibodies and paraoxonase-1 polymorphism in rheumatoid arthritis 
Background
Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disease, with a worldwide prevalence of 0.5% to 1%. Anti-cyclic citrullinated peptide antibody (anti-CCP-2 Ab) is a marker of choice for diagnosing early and late RA. Anti-oxidant enzymes activity decreases in RA patients. Till now, the relationship between the rheumatoid factor (RF) and anti-CCP-2 Ab, anti-oxidant activity and polymorphism of paraoxenase-1 (PON-1) 192 Q/R in patients with RA has not been investigated. In this study, we aimed to determine the serum level of RF and anti-CCP-2 Ab, PON-1 activity and 192 Q/R polymorphism and arylesterase (ARE) activity in patients with RA. Also, we studied RA markers in different genotypes of PON-1 of RA patients.
Methods
A total of 120 RA patients and 90 healthy persons were subjected to full clinical examinations and routine laboratory tests. PON-1 and ARE activities were determined using an enzymatic spectrophotometric method. PON-1 192 gene polymorphism was determined using polymerase chain reaction based restriction fragment analysis. RF was measured by immunoturbidimetry method and anti-CCP-2 Ab was assayed by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using SPSS for windows 20.0.
Results
The sensitivity and specificity of anti-CCP-2 Ab for the diagnosis of RA were 76.2% and 100% respectively. PON-1 and ARE activities were statistically lower (P <0.001) in the RA group compared to the control group. A negative correlation between RF and anti-CCP-2 Ab levels and PON-1 and ARE activities was found. No significant difference in the genotype distribution between RA patients and healthy persons was detected. RF and anti-CCP-2 Ab levels were higher in RA patients carried RR genotype than in those carried QQ genotype.
Conclusion
High RF and anti-CCP-2 antibody serum levels were found to be associated with decreased PON-1 and ARE activities with no correlation between PON-1 polymorphism and serum levels of RF and anti-CCP-2 Ab in patients with RA. These results may indicate an implication between antioxidant enzymes activity and serum levels of RF and anti-CCP-2 Ab.
doi:10.1186/1471-2474-15-379
PMCID: PMC4247608  PMID: 25406539
Rheumatoid arthritis; Anti-CCP-2 antibodies; Paraoxonase-1 polymorphism; Rheumatoid factor; Arylesterase
15.  Adjusting for HLA-DRβ1 in a genome-wide association analysis of rheumatoid arthritis and related biomarkers 
BMC Proceedings  2009;3(Suppl 7):S12.
Background
There is a long-established association between rheumatoid arthritis and HLA-DRβ1. The shared epitope (SE) allele is an indicator of the presence of any of the HLA-DRβ1 alleles associated with RA. Other autoantibodies are also associated with RA, specifically rheumatoid factor IgM (RFUW) and anti-cyclic citrullinated peptide (anti-CCP).
Methods
Using the Genetic Analysis Workshop 16 North American Rheumatoid Arthritis Consortium genome-wide association data, we sought to find non-HLA-DRβ1 genetic associations by stratifying across SE status, and using the continuous biomarker phenotypes of RFUW and anti-CCP. To evaluate the binary RA phenotype, we applied the recently developed FP test and compared it to logistic regression or a genotype count-based test. We adjusted for multiple testing using the Bonferroni correction, the Q value approach, or permutation-based p-values. A case-only analysis of the biomarkers RFUW and anti-CCP used linear regression and ANOVAs.
Results
The initial genome-wide association analysis using all cases and controls provides substantial evidence of an association on chromosomes 9 and 2 within the immune system-related gene UBXD2. In SE-positive subjects, many single-nucleotide polymorphisms were significant, including some on chromosome 6. Due to very few SE negative cases, we had limited power to detect associations in SE negative subjects. We were also unable to find genetic associations with either RFUW or anti-CCP.
Conclusion
Our analyses have confirmed previous findings for genes PTPN22 and C5. We also identified a novel candidate gene on chromosome 2, UBXD2. Results suggest FP test may be more powerful than the genotype count-based test.
PMCID: PMC2795892  PMID: 20017985
16.  Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: results from a 2-year prospective study 
Introduction
The diagnostic, predictive and prognostic role of anti-cyclic citrullinated peptide (CCP) antibodies in rheumatoid arthritis (RA) patients is widely accepted. Moreover, detection of these antibodies in subjects presenting with undifferentiated arthritis (UA) is associated with a significant risk to develop the disease. On the other hand, clinical and prognostic significance of evaluating anti-CCP levels in subjects with inflammatory arthritis at disease onset has not been fully clarified. The goal of this prospective study is to analyze the value and prognostic significance of anti-CCP titer quantification in UA subjects.
Methods
Serial anti-CCP assays were measured in 192 consecutive patients presenting with UA lasting less than 12 weeks. Clinical and serological data and arthritis outcome were evaluated every 6 months until two years of follow-up.
Results
Anti-CCP positivity, at both low and high titer, and arthritis of hand joints significantly predicted RA at two years, risk increasing in subjects with high anti-CCP titers at baseline. Moreover, time to RA diagnosis was shorter in patients with high anti-CCP2 titers at enrollment with respect to those with low antibody concentration.
Conclusions
Presence of anti-CCP antibodies, at both low and high concentration, is significantly associated with RA development in subjects with recent onset UA. However, time interval from the onset of the first symptoms to the fulfilment of the classification criteria appears to be directly related to the initial anti-CCP level.
doi:10.1186/ar4148
PMCID: PMC3672733  PMID: 23339296
17.  Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis 
Introduction
We and others have previously shown that antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and in a more recent study we reported that individuals who subsequently developed RA had increased concentrations of several cytokines and chemokines years before the onset of symptoms of joint disease. Here we aimed to evaluate the prevalence and predictive values of anti-CCP antibodies of IgG, IgM and IgA isotype in individuals who subsequently developed RA and also to relate these to cytokines and chemokines, smoking, genetic factors and radiographic score.
Methods
A case-control study (1:4 ratio) was nested within the Medical Biobank and the Maternity cohorts of Northern Sweden. Patients with RA were identified from blood donors predating the onset of disease by years. Matched controls were selected randomly from the same registers. IgG, IgA and IgM anti-CCP2 antibodies were determined using EliA anti-CCP assay on ImmunoCAP 250 (Phadia AB, Uppsala, Sweden).
Results
Of 86 patients with RA identified as blood donors prior to the onset of symptoms, samples were available from 71 for analyses. The median (Q1 to Q3) predating time was 2.5 years (1.1 to 5.9 years). The sensitivity of anti-CCP antibodies in the pre-patient samples was 35.2% for IgG, 23.9% for IgA, and 11.8% for IgM. The presence of IgG and IgA anti-CCP antibodies was highly significant compared with controls. IgG and IgA anti-CCP2 predicted RA significantly in conditional logistic regression models odds ratio (OR) = 94.1, 95% confidence interval (CI) 12.7 to 695.4 and OR = 11.1, 95% CI 4.4 to 28.1, respectively, the IgM anti-CCP showed borderline significance OR = 2.5 95% CI 0.9 to 6.3. Concentrations of all anti-CCP isotypes increased the closer to the onset of symptoms the samples were collected with an earlier and higher increase for IgG and IgA compared with IgM anti-CCP. IgA and IgG anti-CCP positive individuals had different patterns of up-regulated chemokines and also, smoking brought forward the appearance of IgA anti-CCP antibodies in pre-RA individuals.
Conclusions
Anti-CCP2 antibodies of both the IgG and IgA isotypes pre-dated the onset of RA by years; also, both IgG and IgA anti-CCP2 antibodies predicted the development of RA, with the highest predictive value for IgG anti-CCP2 antibodies.
doi:10.1186/ar3237
PMCID: PMC3241357  PMID: 21291540
18.  Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project) 
Annals of the Rheumatic Diseases  2004;63(9):1085-1089.
Objectives: To evaluate the diagnostic sensitivity of antibodies to cyclic citrullinated peptide (CCP) in recent onset rheumatoid arthritis (RA) at diagnosis and 3 years later, and to evaluate anti-CCP antibody as a predictor of the disease course during 3 years.
Methods: 242 patients with recent onset (⩽1 year) RA were followed up regularly during 3 years after inclusion in the Swedish multicentre study "TIRA" 1996–98. Anti-CCP antibodies were analysed by an enzyme immunoassay (EIA). Rheumatoid factors (RFs) were analysed by latex agglutination and two isotype-specific (IgM and IgA) EIAs. Disease activity was assessed by plasma CRP, ESR, 28 joint disease activity score, and the physician's global assessment of disease activity. Functional ability was evaluated by the Health Assessment Questionnaire.
Results: Overall, the diagnostic sensitivity of anti-CCP antibodies was 64% and the proportion of positive tests increased with the number of fulfilled classification criteria according to the American College of Rheumatology. The anti-CCP antibody results correlated with RF, but were better than RF as predictor of a more aggressive disease course. After 3 years 5/97 patients had changed anti-CCP status: 2 from negative to positive and 3 from positive to negative. The mean level of anti-CCP antibodies declined by 131 U/ml during the 3 year follow up (95% CI 34 to 228 U/ml).
Conclusion: The anti-CCP antibody assay has a similar diagnostic sensitivity to that of RF in early RA, but is better as a predictor of the disease course over 3 years. Although the mean serum level declines, anti-CCP antibody positivity remains essentially unaltered 3 years after diagnosis and start of antirheumatic treatment.
doi:10.1136/ard.2003.016808
PMCID: PMC1755123  PMID: 15308517
19.  Anti-cyclic citrullinated peptide antibodies in primary Sjögren syndrome may be associated with non-erosive synovitis 
Introduction
The purpose of this study was to investigate the prevalence of cyclic citrullinated peptide antibodies (anti-CCP) in patients with primary Sjögren syndrome (pSS) and its correlation with clinical and laboratory data.
Methods
We analysed the clinical and serological data of 155 consecutive patients with pSS. Among these, 14 were excluded due to fulfillment of American College of Rheumatology criteria for rheumatoid arthritis (RA). So, 141 patients (27 males and 114 females; mean age 48 years, range 39 to 60) were clinically assessed for the presence of synovitis (objective swelling of one or more joints) and extra-glandular involvement. The anti-CCP antibodies were tested using a commercially available second-generation enzyme-linked immunosorbent assay. IgM rheumatoid factor (RF) was determined by nephelometry.
Results
Fourteen patients (9.9%) had moderate to high levels of anti-CCP, and 94 (66.7%) were positive for RF. Eighty-one (57.4%) showed extra-glandular involvement, and 44 (31.2%) had synovitis without any radiographic sign of erosion. There was a close correlation between the presence of anti-CCP and synovitis (P < 0.001) but no association between anti-CCP and extra-glandular involvement (P = 0.77). Multivariate analysis confirmed the association between anti-CCP and an increased prevalence of synovitis (prevalence odds ratio for positive versus negative anti-CCP status 7.611, 95% confidence interval 1.475 to 74.870; P = 0.010).
Conclusion
Only a minority of patients with pSS are anti-CCP-positive, which seems to be closely associated with the prevalence of synovitis. Anti-CCP positivity in patients with pSS therefore may be a predictor of future progress to RA or an expression of the inflammatory process of synovial tissue.
doi:10.1186/ar2420
PMCID: PMC2483440  PMID: 18462485
20.  Long-term stability of anti-cyclic citrullinated peptide antibody status in patients with early inflammatory polyarthritis 
Arthritis Research & Therapy  2012;14(3):R109.
Introduction
The utility of reassessing anti-cyclic citrullinated peptide (anti-CCP) antibody status later in disease in patients presenting with early undifferentiated inflammatory polyarthritis, particularly in those who test negative for both anti-CCP and rheumatoid factor (RF) at baseline, remains unclear. We aimed therefore to determine the stability of CCP antibody status over time and the prognostic utility of repeated testing in subjects with early inflammatory polyarthritis (IP).
Methods
Anti-CCP and RF were measured at baseline and 5 years in 640 IP patients from the Norfolk Arthritis Register, a primary care-based inception cohort. The relation between change in anti-CCP status/titer and the presence of radiologic erosions, the extent of the Larsen score, and Health Assessment Questionnaire (HAQ) score by 5 years was investigated.
Results
With a cut-off of 5 U/ml, 28% subjects tested positive for anti-CCP antibodies, 29% for RF, and 21% for both at baseline. Nine (2%) anti-CCP-negative patients seroconverted to positive, and nine (4.6%) anti-CCP-positive individuals became negative between baseline and 5 years. In contrast, RF status changed in 17% of subjects. However, change in RF status was strongly linked to baseline anti-CCP status and was not independently associated with outcome. Ever positivity for anti-CCP antibodies by 5 years did not improve prediction of radiographic damage compared with baseline status alone (accuracy, 75% versus 74%). A higher baseline anti-CCP titer (but not change in anti-CCP titer) predicted worse radiologic damage at 5 years (P < 0.0001), even at levels below the cut-off for anti-CCP positivity. Thus, a titer of 2 to 5 U/ml was strongly associated with erosions by 5 years (odds ratio, 3.6 (1.5 to 8.3); P = 0.003).
Conclusions
Repeated testing of anti-CCP antibodies or RF in patients with IP does not improve prognostic value and should not be recommended in routine clinical practice.
doi:10.1186/ar3834
PMCID: PMC3446486  PMID: 22571727
21.  Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients 
Annals of the Rheumatic Diseases  2012;71(12):1984-1990.
Introduction
There are now over 30 confirmed loci predisposing to rheumatoid arthritis (RA). Studies have been largely undertaken in patients with anticyclic citrullinated peptide (anti-CCP) positive RA, and some genetic associations appear stronger in this subgroup than in anti-CCP negative disease, although few studies have had adequate power to address the question. The authors therefore investigated confirmed RA susceptibility loci in a large cohort of anti-CCP negative RA subjects.
Methods
RA patients and controls, with serological and genetic data, were available from UK Caucasian patients (n=4068 anti-CCP positive, 2040 anti-CCP negative RA) and 13,009 healthy controls. HLA-DRB1 genotypes and 36 single nucleotide polymorphisms were tested for association between controls and anti-CCP positive or negative RA.
Results
The shared epitope (SE) showed a strong association with anti-CCP positive and negative RA, although the effect size was significantly lower in the latter (effect size ratio=3.18, p<1.0E-96). A non-intronic marker at TNFAIP3, GIN1/C5orf30, STAT4, ANKRD55/IL6ST, BLK and PTPN22 showed association with RA susceptibility, irrespective of the serological status, the latter three markers remaining significantly associated with anti-CCP negative RA, after correction for multiple testing. No significant association with anti-CCP negative RA was detected for other markers (eg, AFF3, CD28, intronic marker at TNFAIP3), though the study power for those markers was over 80%.
Discussion
In the largest sample size studied to date, the authors have shown that the strength of association, the effect size and the number of known RA susceptibility loci associated with disease is different in the two disease serotypes, confirming the hypothesis that they might be two genetically different subsets.
doi:10.1136/annrheumdis-2011-201225
PMCID: PMC3595982  PMID: 22661644
22.  Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy 
Arthritis Research & Therapy  2008;10(6):R142.
Introduction
Antibodies against cyclic citrullinated peptides (CCPs) are useful for diagnosing rheumatoid arthritis (RA). Antibodies to mutated citrullinated vimentin (MCV) were described recently in RA. The aims of this study were to evaluate the usefulness of anti-MCV for diagnosing RA in anti-CCP-negative patients and to monitor anti-MCV titres during infliximab therapy for RA.
Methods
We studied two groups of RA patients, one with (n = 80) and one without (n = 76) anti-CCP antibodies. The specificity of anti-MCV was evaluated by investigating 50 healthy controls and 158 patients with other rheumatic diseases (51 psoriatic rheumatism, 58 primary Sjögren syndrome, and 49 ankylosis spondylitis). Serum anti-MCV and anti-CCP titres were measured in 23 patients after 6, 12, 18, and 24 months of infliximab treatment. Anti-CCP2 and anti-MCV levels were assayed using a commercial enzyme-linked immunosorbent assay. IgM rheumatoid factor was determined by nephelometry.
Results
In accordance with the cutoff values recommended by the manufacturer, the specificity of anti-MCV antibodies was 90.9%. We adjusted the cutoff values to obtain the same specificity as that of anti-CCP antibodies (94.2%). With this optimal cutoff, anti-MCV antibodies were found in 11.8% (9/76) of RA patients without anti-CCP, and similarly, anti-CCP antibodies were found in 11.2% (9/80) of RA patients without anti-MCV. Anti-MCV antibodies were positive in 6 patients who tested negative for both anti-CCP and rheumatoid factor. Anti-MCV titres were significantly decreased after 18 and 24 months of infliximab therapy compared with baseline (P < 0.01) as a significant decrease of anti-CCP levels occurred only at 24 months (P < 0.04). Moreover, an anti-MCV decrease was significantly associated with DAS28 (disease activity score using 28 joint counts) improvements 12 months into therapy.
Conclusions
Our results suggest that anti-MCV antibodies may be valuable for diagnosing RA in anti-CCP-negative patients without replacing them as an equivalent number of anti-CCP-positive RA patients test negative for anti-MCV. Moreover, anti-MCV antibodies could be useful for monitoring the effects of infliximab therapy.
doi:10.1186/ar2570
PMCID: PMC2656247  PMID: 19077182
23.  Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis 
Arthritis Research & Therapy  2005;7(5):R949-R958.
Antibodies to citrullinated proteins (anti-cyclic-citrullinated peptide [anti-CCP] antibodies) are highly specific for rheumatoid arthritis (RA) and precede the onset of disease symptoms, indicating a pathogenetic role for these antibodies in RA. We recently showed that distinct genetic risk factors are associated with either anti-CCP-positive disease or anti-CCP-negative disease. These data are important as they indicate that distinct pathogenic mechanisms are underlying anti-CCP-positive disease or anti-CCP-negative disease. Likewise, these observations raise the question of whether anti-CCP-positive RA and anti-CCP-negative RA are clinically different disease entities. We therefore investigated whether RA patients with anti-CCP antibodies have a different clinical presentation and disease course compared with patients without these autoantibodies. In a cohort of 454 incident patients with RA, 228 patients were anti-CCP-positive and 226 patients were anti-CCP-negative. The early symptoms, tender and swollen joint count, and C-reactive protein level at inclusion, as well as the swollen joint count and radiological destruction during 4 years of follow-up, were compared for the two groups. There were no differences in morning stiffness, type, location and distribution of early symptoms, patients' rated disease activity and C-reactive protein at inclusion between RA patients with and without anti-CCP antibodies. The mean tender and swollen joint count for the different joints at inclusion was similar. At follow-up, patients with anti-CCP antibodies had more swollen joints and more severe radiological destruction. Nevertheless, the distribution of affected joints, for swelling, bone erosions and joint space narrowing, was similar. In conclusion, the phenotype of RA patients with or without anti-CCP antibodies is similar with respect to clinical presentation but differs with respect to disease course.
doi:10.1186/ar1767
PMCID: PMC1257421  PMID: 16207336
24.  Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(11):1450-1455.
Objectives
To find out whether autoantibodies to citrullinated telopeptides of type I and II collagens and to cyclic citrullinated peptides (CCPs) predict the development of rheumatoid arthritis (RA).
Methods
A case‐control study (matched for sex, age and municipality) was nested within a Finnish cohort of 19072 adults who had neither arthritis nor a history of it at the baseline examination during 1973–7. 124 subjects developed RA by late 1989, and of these, 89 were positive for rheumatoid factor (RF). Preillness serum specimens were analysed for autoantibodies against arginine (A)‐ or citrulline (C)‐containing synthetic telopeptides using a chemiluminescence method and for anti‐CCPs Mark2 with an enzyme‐linked immunosorbent assay method.
Results
The mean levels of autoantibodies to citrulline‐containing telopeptides and the C/A ratios of type I and II collagens and to CCP were higher in subjects who later developed RF‐positive RA. In the highest tertiles of C/A (I), C/A (II) ratios and anti‐CCPs levels, the relative risk of RF‐positive RA was significantly increased. In the multifactorial model, only anti‐CCPs retained its statistical significance. However, the interaction term of C/A (II) ratio and anti‐CCPs proved to be statistically significant (p = 0.02). The subjects ranked into the highest tertiles of both C/A (II) ratio and anti‐CCPs had an odds ratio of 20.06 (95% confidence interval, 4.37 to 92.06) of developing RF‐positive RA compared with those in the lowest tertiles of these antibodies. None of the autoantibodies predicted RF‐negative RA.
Conclusion
Autoantibodies to citrullinated telopeptides of type I and II collagen and to CCPs exert a synergistic effect on the risk of seropositive RA.
doi:10.1136/ard.2006.062919
PMCID: PMC2111613  PMID: 17472989
25.  Rheumatoid Arthritis in the Women's Health Initiative: Methods and Baseline Evaluation 
American Journal of Epidemiology  2014;179(7):917-926.
Second-generation assays for anti-cyclic citrullinated peptide (anti-CCP), a highly sensitive and specific marker for rheumatoid arthritis (RA), have redefined the epidemiology of RA. In the Women's Health Initiative (WHI) RA study (2009–2011), we evaluated the prevalence of anti-CCP positivity among 15,691 (10.2% of 161,808) WHI participants aged 50–79 years who reported RA. Using stored baseline specimens, we measured serum anti-CCP, rheumatoid factor (RF), and antinuclear antibody in a defined sample of 9,988 of black, white, and Hispanic women. In a subset of women, we measured plasma cytokine levels and number of copies of the human leukocyte antigen (HLA)-DRB1 (HLA-DRB1) shared epitope in DNA by means of Luminex polymerase chain reaction typing (Luminex Corporation, Austin, Texas). We validated classification of probable clinical RA in 2 clinics as anti-CCP positivity or self-reported validated use of disease-modifying antirheumatic drugs (DMARDs). The prevalence of anti-CCP positivity was 8.1%, and the prevalence of RF positivity was approximately 16.0%. DMARD use including prednisone was reported by 1,140 (11.4%) participants (841 excluding prednisone) but by 57.5% of anti-CCP-positive women. The prevalence of 2 shared epitopes was also much higher for anti-CCP-positive women (18.2%, as opposed to only 5.5% for women with anti-CCP-negative DMARD-positive RA and 6.6% for anti-CCP-negative, RF-negative DMARD nonusers). Median cytokine levels were much higher for anti-CCP-positive/RF-positive women. Women with anti-CCP-positive RA and anti-CCP-negative RA had different characteristics with regard to HLA shared epitope, cigarette smoking, and inflammation (cytokines).
doi:10.1093/aje/kwu003
PMCID: PMC3969537  PMID: 24569640
cytokines; epidemiologic methods; genetics; rheumatoid arthritis

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