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1.  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.
PMCID: PMC2654848  PMID: 19287509
2.  Rheumatoid arthritis, item response theory, Blom transformation, and mixed models 
BMC Proceedings  2007;1(Suppl 1):S116.
We studied rheumatoid arthritis (RA) in the North American Rheumatoid Arthritis Consortium (NARAC) data (1499 subjects; 757 families). Identical methods were applied for studying RA in the Genetic Analysis Workshop 15 (GAW15) simulated data (with a prior knowledge of the simulation answers). Fifty replications of GAW15 simulated data had 3497 ± 20 subjects in 1500 nuclear families. Two new statistical methods were applied to transform the original phenotypes on these data, the item response theory (IRT) to create a latent variable from nine classifying predictors and a Blom transformation of the anti-CCP (anti-cyclic citrinullated protein) variable. We performed linear mixed-effects (LME) models to study the additive associations of 404 Illumina-genotyped single-nucleotide polymorphisms (SNPs) on the NARAC data, and of 17,820 SNPs of the GAW15 simulated data. In the GAW15 simulated data, the association with anti-CCP Blom transformation showed a 100% sensitivity for SNP1 located in the major histocompatibility complex gene. In contrast, the association of SNP1 with the IRT latent variable showed only 24% sensitivity. From the simulated data, we conclude that the Blom transformation of the anti-CCP variable produced more reliable results than the latent variable from the qualitative combination of a group of RA risk factors. In the NARAC data, the significant RA-SNPs associations found with both phenotype-transformation methods provided a trend that may point toward dynein and energy control genes. Finer genotyping in the NARAC data would grant more exact evidence for the contributions of chromosome 6 to RA.
PMCID: PMC2367565  PMID: 18466457
3.  Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients 
Annals of the Rheumatic Diseases  2012;71(12):1984-1990.
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.
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.
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%.
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.
PMCID: PMC3595982  PMID: 22661644
4.  The use of citrullinated peptides and proteins for the diagnosis of rheumatoid arthritis 
The presence or absence of antibodies to citrullinated peptides/proteins (ACPA) is an important parameter that helps a clinician set a diagnosis of early rheumatoid arthritis and, hence, initiate treatment. There are several commercial tests available to measure ACPA levels, although it can be difficult to decide what the best test for a given clinical question is. We analyzed literature data in which the diagnostic and other properties of various ACPA tests are compared. The results show that for diagnostic purposes the CCP2 test has the highest specificity, the highest sensitivity in stratified studies and the highest positive predictive value. For the prediction of future joint destruction the CCP2, MCV, and CCP3 tests may be used. The ability to predict the likelihood of not achieving sustained disease-modifying antirheumatic drug-free remission was highest for the CCP2 test. Finally, the levels of anti-CCP2 and anti-CCP3 (and possibly anti-mutated citrullinated vimentin) in rheumatoid arthritis patients are not significantly influenced by TNFα blocking agents.
PMCID: PMC2875630  PMID: 20236483
5.  Anti-cyclic citrullinated peptide antibody titer predicts time to rheumatoid arthritis onset in patients with undifferentiated arthritis: results from a 2-year prospective study 
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.
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.
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.
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.
PMCID: PMC3672733  PMID: 23339296
6.  Comparison of Threshold Cutpoints and Continuous Measures of Anti-Cyclic Citrullinated Peptide Antibodies in Predicting Future Rheumatoid Arthritis 
The Journal of rheumatology  2009;36(4):706-711.
Anti-cyclic citrullinated peptide (anti-CCP) antibodies are strongly associated with increased risk of rheumatoid arthritis (RA). While the anti-CCP level is commonly dichotomized for clinical use, the best threshold for and utility of the titer as a continuous variable to predict development of RA are uncertain.
Using data from the Nurses’ Health Study and Nurses’ Health Study II longitudinal cohorts, we examined the sensitivity, specificity, and hazard of RA at various thresholds of the anti-CCP. Incident RA was confirmed using the Connective Tissue Disease Screening Questionnaire and medical record review in 93 women from among 62,437 participants with blood samples. Three controls per case were randomly chosen, matching on cohort, age, and menopausal status. Stored plasma was tested for anti-CCP antibodies with the second-generation Diastat™ ELISA. Five threshold values were assessed for sensitivity, specificity, and time to diagnosis of RA. Hazard of RA was assessed with conditional logistic regression models adjusting for smoking and reproductive factors.
Using the suggested threshold of > 5 U/ml for anti-CCP positivity, specificity was 100%, but sensitivity was only 28%. A threshold of > 2 U/ml had a higher sensitivity (51%), and similar specificity (80%), with an odds ratio of 11.2 (95% confidence interval 4.7–26.9) for RA. Anti-CCP level as an ordinal variable was strongly associated with time to RA onset, with higher values predicting shorter time to RA onset.
A lower threshold for anti-CCP positivity was more sensitive in predicting RA development. Higher ranges of the level were informative in predicting time to RA onset.
PMCID: PMC3108039  PMID: 19228654
7.  Anti-CCP Revised Criteria for the Classification of Rheumatoid Arthritis 
Annals of the rheumatic diseases  2008;67(11):1557-1561.
Classification of rheumatoid arthritis (RA) is increasingly important as new therapies can halt the disease in its early stages. Antibodies to cyclic citrullinated peptides (anti-CCP) are widely used for RA diagnosis, but are not in the 1987 American College of Rheumatology (ACR) Criteria for RA Classification. We developed and tested the performance characteristics of new criteria for RA classification, incorporating anti-CCP.
We identified all subjects seen in our Arthritis Center with rheumatoid factor (RF) and anti-CCP tested simultaneously between January 1 and June 30, 2004 and reviewed their medical records for the ACR criteria, rheumatologists' diagnoses, RF and anti-CCP. We revised the ACR criteria in two ways: (1) adding anti-CCP, (2) replacing rheumatoid nodules and erosions with anti-CCP (CCP 6 criteria). We compared sensitivity and specificity of all criteria, in all subjects and in subjects with arthritis symptoms ≤ 6 months.
Medical records of 292 subjects were analysed: mean age was 54 years, 82% were women, and mean symptom duration was 4.1 years. 17% were RF+ and 14% were anti-CCP+ at initial testing. 78 (27%) had definite RA per treating rheumatologist at latest follow-up.
The CCP 6 criteria increased sensitivity for RA classification for all subjects regardless of symptom duration: 74% vs. 51% for ACR criteria with a loss in specificity (81% vs. 91%). Sensitivity was greatly improved in subjects with symptoms ≤ 6 months: 25% vs. 63% for ACR criteria with a decrease in specificity.
The CCP 6 criteria improved upon the sensitivity of the ACR criteria, most remarkably for subjects with symptoms ≤ 6 months and could be used for classification of subjects for RA in clinical studies.
PMCID: PMC2964864  PMID: 18234714
Rheumatoid arthritis; cyclic citrullinated peptide; classification; early RA
8.  Anti-Cyclic Citrullinated Peptide Antibody: An Early Diagnostic and Prognostic Biomarker of Rheumatoid Arthritis 
To evaluate the role of Anti-Cyclic Citrullinated Peptide (anti-CCP) antibody and Rheumatoid Factor (RF) in Rheumatoid Arthritis (RA) patients.
The present study comprised of 60 clinically diagnosed rheumatoid arthritis patients and 30 apparently healthy subjects as controls. Among 60 RA patients, 30 were <2 years duration and 30 were 3 to 15 years duration. Anti-CCP and RF levels were analyed by ELISA and immunoturbidimetric assay respectively. Disease activity was assessed by disease duration, duration of morning stiffness, hand deformity and radiological findings. Anti-CCP and rheumatoid factor were measured.
A valid comparison showed that autoantibodies directed to citrullinated antigen–anti-CCP are superior to RF for the detection of RA. Anti-CCP antibodies have an independent role in predicting radiological damage and progression in RA patients.
With their excellent specificity, anti-CCP antibodies can be used as serological marker in establishing the diagnosis of RA. Anti-CCP antibodies discriminated accurately between erosive and nonerosive RA making them a potentially good prognostic marker for the disease.
PMCID: PMC3471491  PMID: 23205355
Rheumatoid arthritis; Anti-cyclic citrullinated peptide antibodies; Rheumatoid factor
9.  Anti-CCP Antibodies Are Not Associated with Familial Mediterranean Fever in Childhood 
Objective. Anticyclic citrullinated peptide antibodies (anti-CCP) testing is useful in the diagnosis of rheumatoid arthritis (RA) with high specificity. Arthritis is a very common clinical manifestation in children with familial Mediterranean fever (FMF). The aim of the study was to show the presence of anti-CCP antibodies in child individuals diagnosed with FMF. Material and Methods. The study groups comprised one hundred and twenty-six patients (126) diagnosed with FMF (female/male (n): 66/60) and 50 healthy controls (female/male (n): 25/25). Clinical and laboratory assessments of the FMF patients were performed during attack-free periods. Erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), fibrinogen, and anti-CCP antibody levels were measured. Results. Anti-CCP was negative in healthy controls and also in all FMF patients. There was not a significant difference in anti-CCP between the patient and the control groups. Our study has shown that anti-CCP was correlated moderately with age (rs = 0.271; P = 0.0020), duration of illness (rs = 0.331; P < 0.0001), and colchicine therapy (rs = 0.259; P = 0.004). Conclusion. Our data show that anti-CCP antibodies are not associated with FMF. Anti-CCP does not have a priority for identifying FMF arthritis from the other inflammatory arthritis.
PMCID: PMC3782833  PMID: 24106502
10.  Anti-Cyclic Citrullinated Peptide, Rheumatoid Factor, and Ocular Symptoms Typical of Rheumatoid Arthritis 
To correlate the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) with ocular symptoms typical of rheumatoid arthritis (RA).
The records of 451 patients who had been examined by an ophthalmologist and tested for anti-CCP antibodies over a 3-year period at the Mayo Clinic were reviewed. Records of 255 patients with titers of anti-CCP and RF were analyzed for ocular surface and inflammatory disease associated with ocular RA.
Of the 33 anti-CCP+/RF+ patients, all were diagnosed with RA; ocular surface disease was present in 11 (33%) and inflammatory disease in 7 (21%). Of the 17 anti-CCP–/RF+ patients, 4 were diagnosed with an unspecified inflammatory arthritis and 1 with rheumatoid arthritis; a separate 5 (29%) had ocular surface disease. Out of 5 anti-CCP+/RF– patients, 3 were diagnosed with RA but none had ocular symptoms. Out of 200 anti-CCP–/RF– patients, 32 (16%) had ocular surface disease and 2 (1%) had ocular inflammation. Of the 74 patients diagnosed with any form of inflammatory arthritis, anti-CCP+/RF+ patients had more and worse inflammatory ocular RA disease compared to the other groups.
Patients who were both anti-CCP and RF positive tended to have more and worse ocular disease. In patients diagnosed with an inflammatory arthritis, the presence of anti-CCP antibodies and RF provides useful information to ophthalmologists for identifying patients most at risk for inflammatory ocular disease.
PMCID: PMC2646447  PMID: 19277223
11.  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.
PMCID: PMC1755603  PMID: 15695535
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.  TRAF1-C5 as a Risk Locus for Rheumatoid Arthritis — A Genomewide Study 
The New England journal of medicine  2007;357(12):1199-1209.
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.
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).
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).
A common genetic variant at the TRAF1-C5 locus on chromosome 9 is associated with an increased risk of anti-CCP-positive rheumatoid arthritis.
PMCID: PMC2636867  PMID: 17804836
14.  Identification of correlated genetic variants jointly associated with rheumatoid arthritis using ridge regression 
BMC Proceedings  2009;3(Suppl 7):S67.
Using the North American Rheumatoid Arthritis Consortium genome-wide association dataset, we applied ridged, multiple least-squares regression to identify genetic variants with apparent unique contributions to variation of anti-cyclic citrullinated peptide (anti-CCP), a newly identified clinical risk factor for development of rheumatoid arthritis. Within a 2.7-Mbp region on chromosome 6 around the well studied HLA-DRB1 locus, ridge regression identified a single-nucleotide polymorphism that was associated with anti-CCP variation when including the additive effects of other single-nucleotide polymorphisms in a multivariable analysis, but that showed only a weak direct association with anti-CCP. This suggests that multivariable methods can be used to identify potentially relevant genetic variants in regions of interest that would be difficult to detect based on direct associations.
PMCID: PMC2795968  PMID: 20018061
15.  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.
PMCID: PMC1257421  PMID: 16207336
16.  Contribution of anti‐cyclic citrullinated peptide antibody and rheumatoid factor to the diagnosis of arthropathy in haemochromatosis 
Annals of the Rheumatic Diseases  2007;66(9):1249-1251.
To investigate the prevalence of antibodies to cyclic citrullinated peptide (anti‐CCP) and rheumatoid factor in patients with hereditary haemochromatosis (HHC) and to evaluate their diagnostic reliability in distinguishing HHC‐associated arthropathy from rheumatoid arthritis.
Anti‐CCP antibodies and rheumatoid factor levels were determined by ELISA in sera from 87 patients with HHC homozygous for the C282Y mutation of the HFE gene, 31 patients with rheumatoid arthritis and 162 healthy controls.
Of the 87 patients with HHC, 32 (36.8%) had joint involvement. Anti‐CCP antibodies were detected in only 1 patient (1.1%) with HHC, who had no joint disease, and in (1.2%) healthy controls. In total, 18 (58.1%) patients with rheumatoid arthritis displayed anti‐CCP reactivity (p<0.001). Rheumatoid factor was detected in 10 (11.5%) patients with HHC compared with 7 (4.3%) healthy control subjects (p = 0.03) and 21 of 31 (65.6%) patients with rheumatoid arthritis.
Testing for anti‐CCP antibodies discriminates HHC arthropathy from rheumatoid arthritis, as these patients were consistently anti‐CCP negative. Thus, HHC arthropathy should be considered in the differential diagnosis of CCP‐negative arthritis.
PMCID: PMC1955139  PMID: 17456529
haemochromatosis; arthropathy; anti‐CCP; rheumatoid factor
17.  Can anti-cyclic citrullinated peptide antibody-negative RA be subdivided into clinical subphenotypes? 
Arthritis Research & Therapy  2011;13(5):R180.
Studies investigating genetic risk factors for susceptibility to rheumatoid arthritis (RA) studied anti-citrullinated peptide antibody (CCP)-positive RA more frequently than anti-CCP-negative RA. One of the reasons for this is the perception that anti-CCP-negative RA may include patients that fulfilled criteria for RA but belong to a wide range of diagnoses. We aimed to evaluate the validity of this notion and explored whether clinical subphenotypes can be discerned within anti-CCP-negative RA.
The 318 patients with anti-CCP-negative RA (1987 ACR criteria), included in the Leiden Early Arthritis Clinic between 1993 and 2006, were studied for baseline characteristics and radiologic progression data during a mean follow-up of 5 years. Grouping was studied both at variable and patient levels. Principal components analysis and partial least-squares regression were applied to study for clustering of variables. A cluster analysis was performed to look for clustering of patients.
The simultaneous presence of patient characteristics at disease presentation was observed for several groups; however, the three largest groups of patients' characteristics explained only 26.5% of the total variance. Plotting the contribution of each patient to these three groups did not reveal clustering of patients. Comparable observations were made when data on progression of joint destruction were studied in relation to baseline clinical data. A cluster analysis, evaluating whether patients resemble each other, revealed no grouping of patients. Altogether, no clinically distinguishable subphenotypes were observed.
The current data provide evidence that, for risk-factor studies, anti-CCP-negative RA patients can be studied as one group.
PMCID: PMC3308115  PMID: 22032620
18.  Evidence of linkage to chromosome 1 for early age of onset of rheumatoid arthritis and HLA marker DRB1 genotype in NARAC data 
BMC Proceedings  2007;1(Suppl 1):S78.
Focusing on chromosome 1, a recursive partitioning linkage algorithm (RP) was applied to perform linkage analysis on the rheumatoid arthritis NARAC data, incorporating covariates such as HLA-DRB1 genotype, age at onset, severity, anti-cyclic citrullinated peptide (anti-CCP), and life time smoking. All 617 affected sib pairs from the ascertained families were used, and an RP linkage model was used to identify linkage possibly influenced by covariates. This algorithm includes a likelihood ratio (LR)-based splitting rule, a pruning algorithm to identify optimal tree size, and a bootstrap method for final tree selection.
The strength of the linkage signals was evaluated by empirical p-values, obtained by simulating marker data under null hypothesis of no linkage. Two suggestive linkage regions on chromosome 1 were detected by the RP linkage model, with identified associated covariates HLA-DRB1 genotype and age at onset. These results suggest possible gene × gene and gene × environment interactions at chromosome 1 loci and provide directions for further gene mapping.
PMCID: PMC2367509  PMID: 18466580
19.  Anti-Cyclic Citrullinated Peptide (Anti-CCP) and Anti-Mutated Citrullinated Vimentin (Anti-MCV) Relation with Extra-Articular Manifestations in Rheumatoid Arthritis 
Journal of Immunology Research  2014;2014:536050.
We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) with the presence of extra-articular (ExRA) manifestations in 225 patients with rheumatoid arthritis (RA). Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group (P = 0.40 and P = 0.91, resp.). Making an analysis of individual manifestations, rheumatoid nodules were associated with positivity for rheumatoid factor (RF); (P = 0.01), anti-CCP (P = 0.048), and anti-MCV (P = 0.02). Instead, RF, anti-CCP, or anti-MCV were not associated with SS, chronic anemia, or peripheral neuropathy. Levels of anti-CCP correlated with the score of the Health Assessment Questionnaire-Disability Index (HAQ-Di) (r = 0.154, P = 0.03), erythrocyte sedimentation rate (ESR); (r = 0.155, P = 0.03), and RF (P = 0.254, P < 0.001), whereas anti-MCV titres only correlated with RF (r = 0.169, P = 0.02). On adjusted analysis, ExRA was associated with longer age (P = 0.015), longer disease duration (P = 0.007), higher DAS-28 score (P = 0.002), and higher HAQ-DI score (P = 0.007), but serum levels of anti-CCP and anti-MCV were not associated. These findings show the need to strengthen the evaluation of the pathogenic mechanisms implied in each specific ExRA manifestation.
PMCID: PMC3997885  PMID: 24804270
20.  Diagnostic value of anti-cyclic citrullinated peptide antibodies in Greek patients with rheumatoid arthritis 
Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been of diagnostic value in Northern European Caucasian patients with rheumatoid arthritis (RA). In these populations, anti-CCP antibodies are associated with the HLA-DRB1 shared epitope. We assessed the diagnostic value of anti-CCP antibodies in Greek patients with RA where the HLA shared epitope was reported in a minority of patients.
Using an enzyme-linked immunosorbent assay (ELISA) (CCP2) kit, we tested anti-CCP antibodies in serum samples from 155 Greek patients with RA, 178 patients with other rheumatic diseases, and 100 blood donors. We also determined rheumatoid factor (RF) and compared it to anti-CCP antibodies for area under the curve (AUC), sensitivity, specificity and likelihood ratios.
Sensitivity of anti-CCP2 antibodies and RF for RA was 63.2% and 59.1%, and specificity was 95.0% and 91.2%, respectively. When considered simultaneously, the AUC for anti-CCP antibodies was 0.90 with 95% CI of 0.87 to 0.93 and the AUC for RF was 0.71 with 95% CI of 0.64 to 0.77. The presence of both antibodies increased specificity to 98.2%. Anti-CCP antibodies were positive in 34.9% of RF-negative RA patients. Anti-CCP antibodies showed a correlation with the radiographic joint damage. Anti-CCP-positive RA patients had increased the swollen joint count and serum CRP concentration compared to anti-CCP-negative RA patients (Mann-Whitney U test, p = 0.01, and p < 0.001, respectively). However, no correlation was found between anti-CCP antibodies and DAS28 score (r = 0.13, p = 0.12).
In Greek patients with RA, anti-CCP2 antibodies exhibit a better diagnostic value than RF and a correlation with radiological joint damage and therefore are useful in everyday rheumatology practice.
PMCID: PMC1876231  PMID: 17448247
21.  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.
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.
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).
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.
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.
PMCID: PMC2803319  PMID: 19884269
22.  Anti-CCP: History and its Usefulness 
Antibodies directed to cyclic citrullinated peptides (anti-CCP) are highly specific for rheumatoid arthritis (RA) and can easily be detected in sera by using commercially available immunoassays. The second version of the anti-CCP test (anti-CCP2) demonstrated high specificity (89-98%) and good sensitivity (41-88%) for RA. Commercially available ELISA methods from three different companies are on the market. All three CCP2 assays show similar results as all CCP2 assays use the same antigen-coated plates. This study was an evaluation of a new automated method for the determination of anti-CCP2 in a routine laboratory setting. Five hundred and fourty three serum samples were tested for anti-CCP2 within normal routine diagnostic using a commercially available ELISA and retested with a prelaunch version of a new and fully-automated method (EliA™). The results were comparable. The new automated assay is easy to use and demonstrated a diagnostic sensitivity of 80% and specificity of 97%.
PMCID: PMC2270729  PMID: 16050144
23.  The likelihood of persistent arthritis increases with the level of anti-citrullinated peptide antibody and immunoglobulin M rheumatoid factor: a longitudinal study of 376 patients with very early undifferentiated arthritis 
We wanted to assess the importance of the levels of anti-citrullinated peptide antibody (anti-CCP) and immunoglobulin M (IgM) rheumatoid factor (RF) in predicting development of persistent arthritis from undifferentiated arthritis (UA), and to investigate whether there is an added predictive value for persistent arthritis in testing for both anti-CCP and IgM RF.
Patients with UA (exclusion of definite non-rheumatoid arthritis (RA) diagnoses) included in the Norwegian very early arthritis clinic were assessed for development of persistent arthritic disease. The effect of antibody level on the likelihood of persistent arthritis was investigated, and the sensitivity and specificity for persistent arthritis for anti-CCP and IgM RF, separately and combined, was determined.
A total of 376 UA patients were included (median arthritis duration 32 days). 59 (15.7%) patients were IgM RF positive, and 62 (16.5%) anti-CCP positive. One hundred, seventy-four (46.3%) had persistent disease after one year. Overlap of anti-CCP and IgM RF positivity was 58%. Sensitivity/specificity for persistent arthritis was 28/95% for IgM RF alone, 30/95% for anti-CCP alone, and 37/92% for positivity of both anti-CCP and IgM RF. The likelihood for persistent disease increased with increasing levels of both anti-CCP and IgM RF.
The likelihood of developing persistent arthritis in UA patients increases with the level of anti-CCP and IgM RF. Testing both anti-CCP and IgM RF has added predictive value in UA patients. This study suggests that antibody level should be taken into account when making risk assessments in patients with UA.
PMCID: PMC2911852  PMID: 20444271
24.  Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis 
Annals of the Rheumatic Diseases  2005;64(8):1199-1204.
Background: The anti-cyclic citrullinated peptide (CCP) test has a high sensitivity and specificity for rheumatoid arthritis, although CCP is not the physiological target of the autoantibodies. Citrullinated fibrin is abundant in inflamed synovium
Objective: To assess the diagnostic and prognostic value of antibodies against citrullinated fibrinogen (ACF), a soluble precursor of fibrin, in comparison with IgM-rheumatoid factor (IgM-RF) and the second generation anti-CCP test.
Methods: In 379 patients with early arthritis (258 rheumatoid and 121 undifferentiated), the sensitivity, specificity, and positive predictive value of ACF, anti-CCP, and IgM-RF for diagnosing rheumatoid arthritis were calculated. Multivariate logistic regression analysis was used to assess the diagnostic and prognostic value (radiographic progression after two years) of the tests.
Results: The sensitivities of the ACF, anti-CCP, and IgM-RF tests were 55.8%, 57.8%, and 44.6%, with specificities of 92.6%, 94.2%, and 96.7%, respectively. Approximately 30% of the IgM-RF negative patients were positive for ACF or anti-CCP or both. The ACF and anti-CCP test had a high agreement in early arthritis (κ = 0.84). Of all baseline characteristics, the ACF test and the anti-CCP test were the best predictors for diagnosing rheumatoid arthritis at one year (odds ratio (OR) = 10.3 and 10.6, respectively) and for radiographic progression after two years (OR = 12.1 and 14.8).
Conclusions: ACF is as sensitive as anti-CCP and more sensitive than IgM-RF in diagnosing rheumatoid arthritis in early arthritis. The ACF test is also a good predictor of radiographic progression, with a performance similar to the anti-CCP test. The ACF test and the anti-CCP test are especially valuable in IgM-RF negative arthritis.
PMCID: PMC1755615  PMID: 15640269
25.  Insights to Clinical Use of Serial Determination in Titers of Cyclic Citrullinated Peptide Autoantibodies 
Mediators of Inflammation  2007;2007:12367.
Anti-cyclic citrullinated peptide (CCP) antibody is a useful marker for the diagnosis and prognosis of rheumatoid arthritis (RA). Recently, clinical significance of follow-up in anti-CCP antibody titer has been pointed out. Thus, we investigated the serial determination in anti-CCP antibodies titer in RA patients. Six patients with RA, who were followed up for longer than 5 years, were assessed in anti-CCP antibodies and radiographs (Larsen score). Anti-CCP antibodies in frozen sera were measured using ELISA. As a result, 6 patients with RA were divided into two groups: one possessed high titers without variation, and the other was without high titers. Joint damage progressed during observation in 2 out of 3 patients with high anti-CCP titers in a retrospective assessment. In contrast, the RA patient, whose anti-CCP titer decreases although it had been high titer at baseline, did not show increase in the Larsen score. These findings suggest that it might be necessary to analyze changes in anti-CCP to predict the prognosis of joint destruction.
PMCID: PMC1847473  PMID: 17497027

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