Anti-cyclic citrullinated peptide (anti-CCP) antibodies in children with juvenile idiopathic arthritis

OBJECTIVE: To determine if anti-cyclic citrullinated peptide antibodies (anti-CCP) can be detected in sera of patients with juvenile idiopathic arthritis (JIA) and if they can be used to identify patients with a more destructive course of disease. METHODS: One hundred serum samples of 71 patients with JIA taken at different time points in their disease course were analyzed by a commercially available anti-CCP ELISA. Followup serum samples from 28 patients were also tested. Correlations between anti-CCP and disease characteristics, medication, and radiological damage (presence of joint space narrowing and/or erosions) were also determined. RESULTS: The serum samples came from patients of all 8 different subtypes of JIA (mean age: 9.6 years, median: 10.5; disease duration mean: 39 months, median: 24) including 11 polyarticular rheumatoid factor positive (IgM-RF) patients. Anti-CCP was positive in 73% of the IgM-RF positive JIA patients and in 3% of the other JIA patients (p < 0.0001). Disease duration, medication, and anti-nuclear antibody positivity did not differ significantly between anti-CCP positive and negative patients. Testing of followup samples showed almost identical anti-CCP results. All IgM-RF positive JIA patients had radiological damage (p < 0.001). Of the anti-CCP positive patients, 80% had radiological damage resulting in a significant difference between anti-CCP positive and negative patients (p = 0.009) with an odds ratio (OR) of 12.7, but corrected for IgM-RF, the OR was no longer significant (p = 0.88). CONCLUSION: Anti-CCP antibodies can be detected in the sera of patients with JIA but almost exclusively in the subset of patients with polyarticular IgM-RF.     

Second generation anti-cyclic citrullinated peptide (anti-CCP2) antibodies can replace other anti-filaggrin antibodies and improve rheumatoid arthritis diagnosis

We compared the diagnostic performance of anti-cyclic citrullinated peptide antibodies detected with second-generation enzyme immunoassay (anti-CCP2) with that of IgM-rheumatoid factor (RF), anti-perinuclear factor (APF), and anti-keratin antibodies (AKA). The sensitivity of anti-CCP2 was better than that of APF and AKA: they were detected in 25% rheumatoid arthritis (RA) patients without detectable APF or AKA. Their specificity, evaluated in other inflammatory rheumatic disease, was similar to that of APF and AKA. Despite the lower specificity, IgM-RF in combination with anti-CCP2 is interesting, as they do not completely overlap. Anti-CCP2 antibody detection seems to be a good alternative to other anti-filaggrin antibodies in the diagnosis of RA.     

Clinical significance of anti-CCP antibodies in rheumatoid arthritis

A number of novel autoantibodies have been recently described in rheumatoid arthritis (RA), and their clinical significance and possible pathogenic roles have been discussed. In particular, new autoantibodies to citrullinated proteins such as filaggrin and its circular form (cyclic citrullinated peptide: CCP) are especially noteworthy because of their high sensitivity and high specificity. There are many studies that anti-CCP antibodies may serve as a powerful serologic marker for early diagnosis of RA and prognostic prediction of joint destruction. Anti-citrullinated protein antibodies are locally produced in RA joints, and citrullinated proteins (most are fibrins) are localized in RA synovial tissue. This finding strongly suggests a possibility that local citrullination of intraarticular proteins might be the initial event leading to autoantibody production in RA. Genetic factors such as a gene polymorphism of the citrullinating enzyme, PADI, might be associated with the breakage of self-tolerance and induction of autoimmunity against citrullinated proteins.     

Relationship of radiological change to clinical outcome in rheumatoid arthritis.

Ninety-four patients with rheumatoid arthritis, seen within the first year after onset, have been followed prospectively with annual radiographs for a mean 63-1 months. An erosive arthropathy occurred in 72. The severity of the erosive changes showed a significant correlation with eventual clinical outcome. It is possible to predict a favourable outcome in those patients whose erosive changes become static at an early stage in the disease.     

Prevalence and clinical significance of antibodies to citrullinated fibrinogen (ACF) in Chinese patients with rheumatoid arthritis

It has been reported that citrullinated fibrin(ogen) deposits in the inflamed joints played an important role in the pathogenesis of rheumatoid arthritis (RA). Although antibodies to citrullinated fibrinogen (ACF) have been detected in the sera of RA patients, the associations between ACF and RA remain unclear. In this study, human fibrinogen was citrullinated by peptidylarginine deiminase in vitro, and the ACF were detected by an enzyme-linked immunosorbent assay in rheumatic patients, including 183 RA, 121 systemic lupus erythematosus, 48 osteoarthritis, and 108 healthy controls. The prevalence of ACF was determined, and the associations between ACF and RA were evaluated. It was shown that the sensitivity and specificity of ACF in RA were 67.21 and 84.84%, respectively. There were significant correlations between ACF and erythrocyte sedimentation rate, anti-cyclic citrullinated peptide antibody, and anti-keratin antibodies (AKA). In radiographic progression, the RA patients with ACF had higher scores than those without ACF according to the Sharp–van der Heijde method. In addition, ACF was often positive in the RA patients who were IgM rheumatoid factor negative or AKA negative or anti-perinuclear factor negative. The results indicate that ACF assay is helpful for the diagnosis of RA.     

Antifilaggrin antibodies in early rheumatoid arthritis may predict radiological progression

OBJECTIVE: To elucidate the possibility that autoantibodies to filaggrin, detected in patients with early RA (having a disease duration of not more than one year), may predict joint destruction assessed after five years of observation. METHODS: This is a 5 yr extension of a previous study (1) of 112 consecutive patients with early RA. Serum antifilaggrin autoantibodies were detected by immunoblotting (AFA) and by indirect immunofluorescence ("AKA"). DAS28, pain on a VAS. HAQ, and CRP were measured. Plain X-ray films were taken from hands and forefeet and a Larsen score was calculated. RESULTS: Ninety-two of the original 112 patients had baseline X-rays available and constituted the study material. At 5 year follow-up, 67 of these 92 have been assessed and for 63 of these X-rays were available. For the whole patient material, significant radiological progression, measured by Larsen scores, occurred while disease activity and function (pain VAS, DAS28, CRP, and HAQ) improved significantly over five years. The groups of patients having AFA or "AKA" at baseline had significantly (p=0.006 and p<0.001, respectively) higher Larsen scores five years later than the groups without these antibodies. No clear relation of these antibodies to disease activity or function was demonstrated, except that the group of patients with "AKA" had significantly higher median CRP (p=0,003) after five years. CONCLUSIONS: The present study shows that antifilaggrin autoantibodies may predict radiological progression. The prognostic value of these antibodies will be further evaluated in relation to other potential markers in a larger patient material.     

Value of antibodies to citrulline-containing peptides for diagnosing early rheumatoid arthritis

OBJECTIVE: To compare the diagnostic values of antiperinuclear factor (APF), antikeratin antibody (AKA), and anti-cyclic citrullinated peptides (anti-CCP) to discriminate between patients with and without rheumatoid arthritis (RA) and to determine the diagnostic value of anti-CCP used alone or with other tests. METHODS: Two hundred and seventy patients with early arthritis underwent standardized investigations in 1995-1997. The clinical utility of APF, AKA, and anti-CCP in first-visit sera was evaluated using receiver-operating characteristic curves. Combinations of anti-CCP with other laboratory tests were assessed by multiple logistic regression. RESULTS: Anti-CCP, APF, and AKA were not perfectly correlated with one another. Anti-CCP with 53 UI as the cutoff was 47% sensitive and 93% specific, versus 52% and 79%, and 47% and 94%, for APF and AKA, respectively. Multiple logistic regression selected anti-CCP, AKA, IgM-rheumatoid factor (RF) ELISA, and the latex test. CONCLUSION: Rheumatologists can routinely use 2 or 3 tests for diagnosing RA (latex and/or IgM RF ELISA, and either AKA or anti-CCP ELISA) and can add a third or fourth test when the diagnosis remains in doubt.     

A comparison of the frequency of antibodies to cyclic citrullinated peptides using a third generation anti-CCP assay (CCP3) in systemic sclerosis, primary biliary cirrhosis and rheumatoid arthritis

The objective was to investigate the frequency of anti-cyclic citrullinated peptides (CCP) antibodies in systemic sclerosis (SSc) and primary biliary cirrhosis (PBC), utilizing a new “third generation” anti-CCP ELISA (anti-CCP3) kit and a conventional anti-CCP2 assay. Patients with PBC, SSc, RA, and normal controls were included in the study. Serum samples were screened for autoantibodies by indirect immunofluorescence (IIF), antibodies to CCP by a second- and third-generation ELISA, antibodies to “scleroderma” antigens (CENP B, Scl-70, PM/Scl and fibrillarin—Scl-34) by a line immunoassay (LIA), and IgM RF by ELISA. The frequency of anti-CCP2 antibodies in SSc and PBC samples was 14.8% (11/74) and 6.2% (5/80), respectively, and the frequency of anti-CCP3 antibodies in SSc was 13.5% (10/74) and in PBC was 3.7% (3/80). By comparison, in the RA group the frequency of anti-CCP3 and anti-CCP2 antibodies was 79.1% (38/48) and 77% (37/48), respectively. Anti-CCP3 ELISA had a sensitivity, specificity, and positive and negative likelihood ratios (LR) of 79% (95% confidence interval [CI] = 64–89%), 93% (95% CI = 88–96%), 11.8 (95% CI = 6.8–20.3), and 0.22 (95% CI = 0.12–0.38), respectively. By comparison, the anti-CCP2 assay had a sensitivity, specificity, and positive and negative LRs of 77% (95% CI = 62–87), 90% (95% CI = 85–94), 8.3 (95% CI = 5.2–13.2), and 0.25 (95% CI = 0.15–0.42), respectively. In patients with SSc, there was an association of anti-CCP2 antibodies with the presence of arthritis, but there was no association of anti-CCP2 or anti-CCP3 with anti-CENP B, anti-Scl 70, or RF. This study confirmed the high specificity and sensitivity of both anti-CCP assays for the diagnosis of RA. The presence of anti-CCP antibodies in SSc was only correlated with the presence of arthritis.     

Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis

OBJECTIVE: To compare the diagnostic utility of anti-cyclic citrullinated peptide (anti-CCP) antibodies with other serological markers including rheumatoid factor (RF), anti-agalactosyl immunoglobulin G (IgG) antibody, and matrix metalloproteinase (MMP)-3 in very early rheumatoid arthritis (RA). METHODS: Serum concentrations of anti-CCP antibodies, RF, anti-agalactosyl IgG antibody, and MMP-3 were measured in 262 patients with RA ("total RA") including 55 patients with disease duration of less than 6 months who had not been treated before entry ("very early RA") and 116 patients with rheumatic diseases other than RA. RESULTS: The diagnostic sensitivity of anti-CCP antibodies was 82.4% in total RA and 67.3% in very early RA and was lower than that of RF (84.0% total RA, 83.6% very early RA) and anti-agalactosyl IgG antibody (90.5%, 90.9%), whereas specificity, positive predictive value, and diagnostic accuracy were the best among markers tested both in total RA and in very early RA. The presence of either anti-CCP antibodies or RF increased the sensitivity, but any combination of serological markers was not significantly better in diagnostic accuracy than anti-CCP antibodies alone. The rates of RF-positive subjects in anti-CCP antibody-negative patients both in total RA (43.5%) and in very early RA (61.1%) were higher than those of anti-CCP antibody-positive subjects in RF-negative patients (38.1% and 22.2%, for total RA and early RA, respectively). CONCLUSION: Measurement of anti-CCP antibodies, by itself, is useful for the diagnosis of RA; however, combined use of anti-CCP antibodies with RF may be more useful than either method alone for the diagnosis of very early RA.     

Diagnostic and prognostic value of antibodies to cyclic citrullinated peptide (Anti-CCP) in rheumatoid arthritis

There is strong evidence that the determination of autoantibodies against filaggrine is a very useful tool for the diagnosis of rheumatoid arthritis (RA). Anti-cyclic citrullinated peptide antibodies (Anti-CCP)-ELISA appear to be the most efficient test among those available for the detection of antifilaggrine autoantibodies, as it has the best diagnostic accuracy for the diagnosis of RA. Furthermore, the anti-CCP-ELISA determination in early arthritis is a good predictor of disease persistence and radiographic joint damage. The positivity of Anti-CCP some years before the onset of the RA and the high concentration of autoantibodies in synovial fluid suggest a possible pathogenetic role of citrullination. However, at present, it is unclear whether anti-CCP antibodies have a better diagnostic performance than rheumatoid factor in recent onset synovitis and if they confer any additional value to the prognostic evaluation obtained with validated predictors of outcome (FR, joint count, duration of disease).     

How to assess early rheumatoid arthritis in daily clinical practice

Rheumatoid arthritis (RA) is a heterogeneous disorder in terms of both clinical presentation and outcome. Our goals in RA are directed towards suppression of signs and symptoms of synovitis, prevention of structural damage, maintenance of functionability and reduction of mortality. IgM rheumatoid factor and anticitrulline antibodies should be recorded in clinical practice since they are prognostic values of outcome. As control of disease activity is pivotal to preventing or at least retarding long-term damage, it is important to define stringent therapeutic aims as well as to follow-up patients in daily practice. The disease activity score 28 is a valuable instrument for this purpose. The assessment of radiographic damage and disability should be assessed regularly. Since increased cardiovascular mortality has been documented even in early RA, other cardiovascular risk factors should be looked for and eventually treated.     

Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis

OBJECTIVE: To study antibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor in patients with active, severe extra-articular rheumatoid arthritis (ExRA) compared with controls without ExRA. METHODS: 35 consecutive patients with severe ExRA manifestations according to predefined criteria were studied. 70 patients with rheumatoid arthritis, but no ExRA manifestations, individually matched for age, sex and disease duration, served as controls. Patients were included when ExRA was diagnosed, before any new treatment was started. Anti-CCPs were detected with ELISA, rheumatoid factor was quantified using nephelometry and anti-nuclear antibodies (ANA) were investigated using indirect immune fluorescence. RESULTS: Anti-CCPs were detected in 77% of patients with ExRA versus 56% of controls without ExRA (p = 0.03). Anti-CCP levels also tended to be higher in patients with ExRA (p = 0.09). Rheumatoid factor was detected in 94% v 71% of patients and controls, respectively (p = 0.006), and rheumatoid factor levels were higher in patients with ExRA (median interquartile range (IQR) 245 IU/ml (94-604) v 73 IU/ml (not detected-165); p = 0.001). Levels and occurrence of ANA did not differ between patients with ExRA and controls. Patients with ExRA had higher swollen joint counts and C reactive protein levels, but no correlations were found between anti-CCP or rheumatoid factor levels and these measures within the ExRA group. CONCLUSION: Rheumatoid factor is strongly associated with severe ExRA manifestations in patients with rheumatoid arthritis, and a similar but weaker association exists for anti-CCPs. This suggests a role for rheumatoid factor and anti-CCP in the pathogenesis of ExRA.     

Anti‐citrullinated protein antibodies and their clinical utility in rheumatoid arthritis

One of the most important serological discoveries in rheumatology in recent years has been the characterization of autoantigens in rheumatoid arthritis (RA) containing the amino acid citrulline. There are many citrullinated proteins in the inflamed RA synovium. Rheumatoid factor (RF), which is the immunologic hallmark of RA, is not specific for RA, as it is found in 5% of healthy individuals and in 10–20% of those over the age of 65 years. RFs are of low titer in early disease stages when a clear diagnosis is often not yet possible; But anti‐citrullinated protein antibodies (ACPAs) can be found early in the disease course of RA, even years before the onset of clinical symptoms. The identification of citrullinated epitopes led to the development of the first and later second generation anti‐cyclic citrullinated peptide (anti‐CCP) antibody assays. Anti‐CCP2 antibody has shown a specificity of 98% in sera from patients with established RA and 96% in sera from subjects with early RA. Anti‐CCP can predict erosive disease, therefore could be a good serological marker for RA diagnosis.     

The role of anti-cyclic citrullinated peptide antibodies in predicting progression of palindromic rheumatism to rheumatoid arthritis

OBJECTIVE: To determine whether the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies at presentation is of prognostic value in patients with palindromic arthritis. METHODS: Stored sera, taken around the time of presentation from patients with palindromic arthritis, where available, were assessed for anti-CCP antibodies, and results were correlated with subsequent clinical outcome. RESULTS:Twenty-nine of 61 patients had progressed to rheumatoid arthritis after a mean followup of 5.4 years; 83% of these had had anti-CCP antibodies in their baseline sera. CONCLUSION: The sensitivity/specificity and likelihood ratios for CCP antibodies were better than rheumatoid factor in predicting outcome.     

The association of anti-CCP antibodies with disease activity in rheumatoid arthritis

Antibodies to citrullinated proteins have been described in patients with rheumatoid arthritis (RA) and these appear to be the most specific markers of the disease. Our objective was to determine the frequency of antibodies to cyclic citrullinated peptides (CCPs) in patients with RA and the association of anti-CCP antibodies with disease activity, radiological erosions and HLA DR genotype. Forty patients with RA and 38 patients with fibromyalgia were included in this study. Serum samples were collected from both patient groups with RA and fibromyalgia. Anti-CCP was measured by the corresponding enzyme-linked immunosorbent assay. Additionally, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), disease activity score (DAS), visual analog scala (VAS), HLA genotype and radiographic information were determined in patients with RA. The rate of sensitivity and specificity of anti-CCP reactivity for the diagnosis RA were measured (sensitivity 50%, specificity 100%). There is no significant difference between anti-CCP (+) and anti-CCP (-) RA patients for DAS28, VAS, ESR, CRP, disease duration, HLA genotype, and radiological assessment of hand. However, there was a significant difference between anti-CCP (+) and anti-CCP (-) RA patients for RF and the radiological assessment of left and right wrists (respectively, P < 0.05, P = 0.04, P = 0.01). There was no significant correlation between anti-CCP antibody and ESR, CRP, VAS, DAS 28 or radiological assessment. A small but significant correlation was found between RF and anti-CCP antibody (P = 0.02, r = 0.35).     

Anti-citrullinated protein antibodies (ACPA) in early rheumatoid arthritis

Autoantibodies with the highest specificity for rheumatoid arthritis (RA) are the antibodies directed to citrulline-containing epitopes, so-called anti-citrullinated peptide/protein antibodies (ACPA). During the past decade it became clear that the presence of these antibodies was highly predictive of and specific for RA, and illustrating the importance of ACPA. Therefore, the presence of these antibodies is one of the new American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for RA. Apart from the presence of these antibodies, the composition of this antibody response matures during RA development. This review summarizes the current knowledge of the characteristics of ACPA in RA development.