Anti-cyclic citrullinated peptide (CCP) antibodies in patients with long-standing rheumatoid arthritis and their relationship with extra-articular manifestations

doi:10.1016/j.clinbiochem.2006.06.004

Clinical Biochemistry

Volume 39, Issue 10, October 2006, Pages 961-965

https://doi.org/10.1016/j.clinbiochem.2006.06.004 Get rights and content

Abstract

Objectives

To evaluate frequency of anti-cyclic citrullinated peptide antibodies (anti-CCP) in long-standing rheumatoid arthritis (LsRA) patients and their relationship with extra-articular manifestations of rheumatoid arthritis (RA), in addition to comparing frequency of anti-CCP antibodies in early RA (ERA) and LsRA group.

Design and Methods

One hundred and fifteen consecutive RA patients were included in the study as having LsRA because their disease duration was longer than 3 years. Thirty-nine consecutive patients with RA were included in the study as having ERA (< 3 years). Also, 64 individuals were included in the study as healthy controls to verify the specificity and sensitivity of anti-CCP antibodies. Anti-CCP antibody and rheumatoid factor (RF) were evaluated with enzyme-linked immunosorbent assay kits and standard nephelometry methods, respectively. Extra-articular manifestations were diagnosed by relevant criteria.

Results

The total number of patients with extra-articular manifestations was found to be 45 (39%). No significant difference was found between LsRA group and ERA group in terms of extra-articular manifestations. There were no differences between both groups regarding the number of patients with positive anti-CCP antibodies and the levels of anti-CCP antibodies. In LsRA group, there was a positive correlation between erosion and disease duration (r = 0.24, p < 0.01), between erosion and RF (r = 0.29, p < 0.002), and between erosion and anti-CCP antibody (r = 0.21, p < 0.02). Positive correlations between RF and anti-CCP antibody (r = 0.32, p < 0.0001), as well as between subcutaneous nodule and lung involvement (r = 0.24, p < 0.008), were found in the LsRA group. However, no positive correlation could be found between anti-CCP antibody positivity and extra-articular organ involvement, either cumulatively or separately.

Conclusions

Although anti-CCP antibodies are associated with the severity of the disease and erosion, they do not seem to have much linkage with extra-articular manifestations of RA.

Introduction

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease of unknown aetiology, characterized by articular and extra-articular involvement as well as rheumatoid factor (RF) positivity. Early diagnosis and early disease modifying anti-rheumatic drug (DMARD) treatment in RA lead to better control and less joint damage. Therefore, it is very important to find an acceptable serological marker or markers in order to make an early precise diagnosis. RF has a moderate sensitivity for the diagnosis of RA and can be positive in other chronic autoimmune and infectious diseases [1]. Another diagnostic test for RA, the assay for anti-cyclic citrullinated peptide antibodies (anti-CCP), has been developed in recent years. These antibodies are directed to proteins that contain the unusual amino acid citrulline, which is derived from the post-translational modification of arginine by peptidylarginine deiminases [2]. Anti-CCP antibodies are highly specific serological markers for RA that are thought to be directly involved in the disease pathogenesis [3]. Apart from the potentially destructive joint manifestations of RA, it is also characterized by extra-articular organ involvement (ExRA). It has been reported that mortality is greater in RA patients with ExRA [4], [5]. Some serological and clinical markers, such as the presence of HLA DRB 0401 [6], antinuclear antibody (ANA) [7], RF [8], as well as subcutaneous nodules [7], are associated with ExRA. Taking into consideration the fact that HLA Class II RA susceptibility alleles are associated with the production of anti-CCP antibodies [9], it would be interesting to investigate whether or not anti-CCP antibodies are related to extra-articular manifestations of RA. The aims of the present study are as follows: (a) to investigate, in the long-standing RA (LsRA) group, whether or not there is a relationship between anti-CCP antibodies and ExRA; (b) to compare the frequency of anti-CCP antibodies in groups of early RA (ERA) and LsRA; and (c) to separately evaluate the specificity and the sensitivity of anti-CCP antibodies and RF in the ERA and the LsRA groups.

Section snippets

Patients

One hundred and fifteen consecutive patients (94 F, 21 M, mean age 53 ± 10) meeting the American College of Rheumatology (ACR) classification criteria for RA [10] were included in the study as having LsRA because their disease duration was longer than 3 years. Thirty-nine consecutive patients (26 F, 13 M, mean age 46 ± 13) with RA were included in the study as having ERA (< 3 years) in order to compare the frequency of anti-CCP antibody between ERA and LsRA patients. Plus, 64 individuals (54 F,

Demographic data

No significant difference was found between groups in terms of gender (p < 0.07). The mean age of LsRA group was higher than ERA and healthy control group (p < 0.0001) (Table 1). As was expected, in LsRA group, disease duration was longer than ERA group (p < 0.0001). (Table 1)

Frequency of erosion and extra-articular manifestations

Erosions were present in 91 (80%) of LsRA patients. The total number of patients with ExRA (lung involvement, subcutaneous nodules, amyloidosis, vasculitis, scleritis, scleromalacia perforance, Felty syndrome) in LsRA group was

Discussion

Our results in patients with LsRA confirm the observations made by other studies in patients with RA in terms of anti-CCP antibodies' relationship with erosion and its specificity [12], [13]. However, we could not find any correlation between anti-CCP antibodies and ExRA.

Although presence of the ExRA in this study was identified as defined before [11], investigation of lung involvement was limited to symptomatic patients and those patients with abnormal chest radiography. It has been reported

References (29)

H. Tighe et al.
Rheumatoid factor
E.R. Vossenaar et al.
Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages
Ann. Rheum. Dis.
(2004)
C.C. Reparon-Schuijt et al.
Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis
Arthritis Rheum.
(2001)
D.L. Vollertsen Conn et al.
Rheumatoid vasculitis. Survival and associated risk factors
Medicine
(1986)
C.C. Erhardt et al.
Factors predicting the prognosis in rheumatoid arthritis: an eight year prospective study
Ann. Rheum. Dis.
(1989)
C.M. Weyand et al.
Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis
J. Clin. Invest.
(1992)
C. Turesson et al.
Predictors of extra-articular manifestations in rheumatoid arthritis
Scand. J. Rheumatol.
(2000)
S. Bas et al.
Association of rheumatoid factors and anti-flaggrin antibodies with severity of erosions in rheumatoid arthritis
Rheumatology
(2000)
F.A. van Gaalen et al.
Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis
Arthritis Rheum.
(2004)
F.C. Arnett et al.
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis
Arthritis Rheum.
(1988)

L. Carmona et al.

Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity

Ann. Rheum. Dis.

(2003)

G.C. Pinheiro et al.

Anti-cyclic citrullinated peptide antibodies in advanced rheumatoid arthritis

Ann. Intern. Med.

(2003)

H. Visser et al.

How to diagnose rheumatoid arthritis early. A prediction model for persistent (erosive) arthritis

Arthritis Rheum.

(2002)

S.H. Zrour et al.

Correlations between high-resolution computed tomography of the chest and clinical function in patients with rheumatoid arthritis. Prospective study in 75 patients

Joint Bone Spine

(2005)

Cited by (52)

Emerging role of innate B1 cells in the pathophysiology of autoimmune and neuroimmune diseases: Association with inflammation, oxidative and nitrosative stress and autoimmune responses
2019, Pharmacological Research
Citation Excerpt :
Levels of anti-CCP are of diagnostic and prognostic value in a similar manner to the serum concentration of RF, which suggests a role in the pathogenesis of the condition [183–185]. However, while high levels of RF are associated with systemic manifestations in RA, no such relationship is seen when measuring levels of anti-CCP antibodies [186]. Moreover, while RF levels consistently fall in patients responding to anti-TNF-α therapy, the response of anti-CCP antibodies is highly inconsistent indicating that this cytokine plays a role in RF production, but not the formation of the anti-CCP-IgG complex [187].
B1 lymphocytes may be subdivided by CD5 and CD11b/Mac1 expression into B1a, with the CD5 and CD11b/Mac1 phenotype, and B1b, which present as CD19^hiCD5^loCD11b^hi. B1b cells share many surface and functional characteristics with marginal zone B cells but differ in distribution and B cell receptor (BCR) signalling pathways. They are normally concentrated in the peritoneum, pleural cavities, spleen and bone marrow and function as efficient phagocytes and antigen-presenting cells (APCs). While peritoneal B1b cells are relatively anergic, they may be activated by high cytokine levels, notably IL-10, IL-5 and IL-21, CD40 signalling and high doses of Toll-like receptor (TLR) ligands in the context of pathogen invasion; TLR ligation is also necessary. Their anti-inflammatory effects include: secretion of natural IgM by splenic and bone marrow B1b cell subsets as an early response to pathogen invasion; tissue homeostasis and enabling the immunologically silent clearance of neoplastic and apoptotic cells; inhibition of pro-inflammatory cytokines and increased production of TGF-β1, PGE₂ and GcMAF by activated macrophages and dendritic cells; and, in the case of peritoneal B1 lymphocytes, acting as ultimate Breg precurors. Pro-inflammatory B1b properties may result from: abnormal trafficking; acting as APCs; and acting as a source of innate-response activator cells. Functional impairment or deficits in Bregs occur in multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis. Details are given of potential pathogenic roles of IgM and B1b lymphocytes in these autoimmune disorders and in deficit-schizophrenia, and how these changes relate to inflammatory and oxidative and nitrosative stress.
Increased circulating Wnt5a protein in patients with rheumatoid arthritis-associated interstitial pneumonia (RA-ILD)
2019, Immunobiology
Citation Excerpt :
Apart from the RF, several serological indexes, such as erythrocyte sedimentation rate (ESR) and cyclic citrullinated peptide antibodies (CCPA) also were reported to have diagnostic values for ILD in RA. For instances, an association between RA-ILD and increased ESR was detected in a group of 52 RA-ILD patients (Koduri et al., 2010), such an association was also identified CCPA and RA-ILD (Inui et al., 2008; Korkmaz et al., 2006). In agreement with their findings, positive correlations between the plasma Wnt5a protein and plasma RF and C-reactive protein (CRP) were detected in this study.
An early diagnosis of interstitial lung disease (ILD) is important for guiding treatments of rheumatoid arthritis (RA)-associated ILD (RA-ILD) in clinical settings. The non-canonical Wnt signaling representative ligand Wnt5a was recently found to involve in idiopathic pulmonary fibrosis (IPF) and pathogenesis of RA. The goal of this study was to examine the clinical relevance of Wnt5a in RA-ILD. In this report, the clinical relevance of plasma Wnt5a protein was evaluated in 40 RA-ILD patients and 41 non-ILD RA cohorts. The results showed an elevated Wnt5a protein in plasmas of RA-ILD patients compared with non-ILD RA patients (p < 0.01), which was positively correlated with the plasma level of rheumatoid factor (RF). Of note, more abundant Wnt5a was also found in patients with usual interstitial pneumonia (UIP) than those with nonspecific interstitial pneumonia (NSIP) and other ILD patterns. More importantly, the disease severity was correlated with the circulating Wnt5a as ascertained by high-resolution computed tomography (HRCT)-UIP scores. The multiple-factor non-conditional logistic regression analysis further revealed that the age, RA duration, smoking and plasma Wnt5a were risk factors with clinical significance for RA-ILD. Interestingly, more Wnt5a-positive patients were identified in RA-ILD smokers relative to RA-ILD never-smokers, and longer smoking duration was strongly correlated with Wnt5a in RA-ILD patients. In consistence, ROC curve also suggested that the Wnt5a was a potential candidate biomarker for identifying patients with RA-UIP. These results demonstrate that the circulating Wnt5a may be a risk factor and potential biomarker for identifying UIP and accessing the severity and progression of ILD in RA patients.
Image analysis of fibrosis in labial salivary glands of patients with systemic autoimmune diseases. Close correlation of lobular fibrosis to seropositive rheumatoid arthritis and increased anti-CCP and RF titres in the serum
2018, Pathology
Citation Excerpt :
The present study is the first which points to the association of lobular fibrosis and higher frequency of RF/anti-CCP autoantibody positivity in the serum, or in clinical terms the association of this with seropositive RA. It is known that anti-CCP positivity has a strong correlation with the articular manifestation of RA and it can predict onset of the disease prior to the appearance of clinical signs and symptoms.36–38 However, correlation between extra-articular organ involvement and anti-CCP positivity has not yet been indicated.38
Lobular fibrosis in labial salivary glands of patients with systemic autoimmune disease is a rarely examined and rather neglected histological change. Its significance and disease association is poorly understood. Our aim was to explore the clinical correlations of fibrosis in labial salivary gland samples using objective methods and laboratory parameters. Labial salivary gland samples from more than 300 patients over a 3-year period were selected from the archives of the pathology department, histologically examined, digitised, image analysed and statistically evaluated to identify the presence and intensity of lobular fibrosis, its relation to age, clinical diagnoses of systemic autoimmune disease and the presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP), antinuclear antibodies (ANAs), and anti-dsDNA serum markers. Significant correlation was found between lobular fibrosis and the presence of autoimmune disease (p = 0.023), mainly seropositive rheumatoid arthritis (p < 0.001). Also significant association was found between the fibrosis and the presence of serum anti-CCP (p < 0.001) and IgA/IgG/IgM-RF (p < 0.001, p < 0.001 and p = 0.008, respectively). Significant association was explored between the anti-dsDNA positivity and the negative histology groups (p = 0.033) and between the ANA positivity and the inflammation only group (p = 0.021). The results suggest that lobular fibrosis tends to associate to certain systemic autoimmune diseases, mainly seropositive rheumatoid arthritis, and seems to be rare in labial salivary gland biopsies of autoimmune diseases characterised by presence of anti-dsDNA. The close correlation of ANA positivity and the inflammation only histology was not surprising, since the majority of patients (62%) have Sjögren's syndrome, known for its inflammatory infiltrate. These findings emphasise that evaluation of lobular fibrosis and inflammation in histological samples of labial salivary gland biopsies are equally important.
Anti-CCP antibodies are not a marker of severity in established rheumatoid arthritis: A magnetic resonance imaging study
2017, Revista Brasileira de Reumatologia
Citation Excerpt :
It is already known that some features, when present, are associated with a worse outcome of the disease, such as the presence of high-titer rheumatoid factor, smoking and HLA-DRB1.1,2 Regarding the prognostic role of anti-CCP, its association with disease activity and functional capacity has still not been clarified, although many studies suggest that these antibodies are associated with more severe and erosive disease,3–22 especially in cases of initial RA.9,19–21,23–30 It is worth noting the methodological heterogeneity of the studies that analyzed the association of anti-CCP with structural damage.
The presence of anti-CCP is an important prognostic tool of rheumatoid arthritis (RA). But research is still ongoing on its relationship with disease activity and functional capacity.
To study the relationship between anti-CCP and disease activity, functional capacity and structural damage indexes, by means of conventional radiography (CR) and magnetic resonance imaging (MRI), in cases of established RA.
Cross-sectional study with RA patients with 1–10 disease duration. Participants underwent clinical evaluation with anti-CCP. Disease activity was assessed using the Clinical Disease Activity Index (CDAI), and functional capacity through the Health Assessment Questionnaire (HAQ). CR analysis was carried out by the Sharp van der Heijde index (SvdH), and MRI analysis by RAMRIS (Rheumatoid Arthritis Magnetic Resonance Image Scoring).
We evaluated 56 patients, with a median (IqR) age of 55 (47.5–60) years; 50 (89.3%) participants were female and 37 (66.1%) were positive for anti-CCP. Medians (IqR) of CDAI, HAQ, SvdH and RAMRIS were 14.75 (5.42–24.97) 1.06 (0.28–1.75), 2 (0–8) and 15 (7–35), respectively. There was no association between anti-CCP and CDAI, HAQ and SvdH and RAMRIS scores.
Our results have not established an association of anti-CCP with the severity of disease. To date, we cannot corroborate anti-CCP as a prognostic tool in patients with established RA.
A presença do anti-CCP constitui importante ferramenta prognóstica da artrite reumatoide (AR). Mas, ainda, investiga-se sua relação com a atividade de doença e a capacidade funcional.
Estudar a relação o anti-CCP e os índices de atividade da doença, de capacidade funcional e de dano estrutural, através de radiografia convencional (RC) e de ressonância magnética (RM), em AR estabelecida.
Estudo transversal com pacientes com AR, com um a 10 anos de doença. Os participantes foram submetidos à avaliação clínica com pesquisa do Anti-CCP. A atividade de doença foi avaliada através Clinical Disease Activity Index (CDAI) e a capacidade funcional através do Health Assessment Questionnaire (HAQ). A análise da RC foi feita pelo índice de Sharp van der Heijde (SmvH) e da RM pelo Sistema de Pontuação de Imagem por Ressonância Magnética na Artrite Reumatoide (RAMRIS, Rheumatoid Arthritis Magnetic Resonance Image Scoring).
Foram avaliados 56 pacientes, com mediana (IIq) de idade de 55 (47,5-60) anos, sendo 50 (89,3%) do sexo feminino e 37 (66,1%) anti-CCP positivos. As medianas (IIq) do CDAI, do HAQ, de SmvH e do RAMRIS foram de 14,75 (5,42-24,97), 1,06 (0,28-1,75), 2 (0-8) e 15 (7-35), respectivamente. Não houve associação do anti-CCP com o CDAI, com o HAQ e com os escores SmvH e RAMRIS.
Nossos resultados não estabeleceram a associação do anti-CCP com a gravidade da doença. Até o momento, não podemos corroborar o anti-CCP como uma ferramenta prognóstica em AR estabelecida.
Anti-citrullinated heat shock protein 90 antibodies identified in bronchoalveolar lavage fluid are a marker of lung-specific immune responses
2014, Clinical Immunology
Citation Excerpt :
Extra-articular disease manifestations represent a significant cause of morbidity and mortality in rheumatoid arthritis (RA) [1–6].
Previous work has demonstrated a correlation between serum anti-citrullinated HSP90 antibodies and rheumatoid arthritis-associated interstitial lung disease (RA-ILD). To further investigate this potential pathogenic relationship, we used ELISA-based techniques to assess anti-citrullinated HSP90 antibody profiles in bronchoalveolar lavage fluid (BALF) of patients with different stages of RA-ILD. 9/21 RA-derived BALF specimens demonstrated IgG and/or IgA antibodies targeting citrullinated HSP90 proteins/peptides, highlighting disease specific responses (with a predilection for RA-ILD) that did not occur in IPF patients (0/5) or healthy control subjects (0/5). Comparison of antibody profiles between BALF and matching serum specimens revealed various recognition patterns favoring predominant production of anti-citrullinated HSP90 antibodies within the lung microenvironment—further supporting the connection between this antibody specificity and parenchymal lung disease. Equally important, qualitative as well as quantitative differences in anti-citrullinated HSP90 profiles between BALF and serum indicate that the lung plays a direct role in shaping the immune repertoire of RA/RA-ILD.
Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis
2012, Respiratory Medicine
Pulmonary disease is a well recognised and important extra-articular manifestation of rheumatoid arthritis (RA). The objective of this study was to determine the prevalence of airway and parenchymal abnormalities in newly diagnosed patients with RA and to correlate these with clinical measures of RA severity and laboratory tests.
60 patients with a new (symptom duration <12 months) diagnosis of RA (43 females, 42 European, mean age 54, 33 ever smoker, (17 current) underwent lung function testing and high resolution computed tomography (HRCT) scored by two independent radiologists.
Eighteen (30%) patients reported respiratory symptoms: dyspnoea (11), cough (11), and wheeze (8). Twelve (20%) patients had physiologic evidence of airflow obstruction and 24 (40%) had reduced gas transfer. The prevalence of HRCT abnormalities (in any lobe) was as follows: decreased attenuation 67%, bronchiectasis 35%, bronchial wall thickening 50%, ground glass opacification 18%, reticular changes 12%. All abnormalities were more common in the lower lobes. With the exception of reduced DLCO, there were no significant differences in the prevalence of HRCT patterns or lung function parameters between smokers and non smokers. Anti-CCP antibodies and rheumatoid factor (RF) correlated strongly with DLCO and variably with other physiologic measures but poorly with radiologic abnormalities.
Patients with newly diagnosed RA have a moderate prevalence of airway and parenchymal abnormalities on HRCT and lower than predicted lung function parameters which cannot entirely be explained by smoking. These data suggest that pulmonary involvement is present early in the disease course in RA.

View all citing articles on Scopus

View full text

Anti-cyclic citrullinated peptide (CCP) antibodies in patients with long-standing rheumatoid arthritis and their relationship with extra-articular manifestations

Abstract

Objectives

Design and Methods

Results

Conclusions

Introduction

Section snippets

Patients

Demographic data

Frequency of erosion and extra-articular manifestations

Discussion

Rheumatoid factor

Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages

Ann. Rheum. Dis.

Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis

Arthritis Rheum.

Rheumatoid vasculitis. Survival and associated risk factors

Medicine

Factors predicting the prognosis in rheumatoid arthritis: an eight year prospective study

Ann. Rheum. Dis.

Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis

J. Clin. Invest.

Predictors of extra-articular manifestations in rheumatoid arthritis

Scand. J. Rheumatol.

Association of rheumatoid factors and anti-flaggrin antibodies with severity of erosions in rheumatoid arthritis

Rheumatology

Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

Arthritis Rheum.

The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

Arthritis Rheum.

Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity

Ann. Rheum. Dis.

Anti-cyclic citrullinated peptide antibodies in advanced rheumatoid arthritis

Ann. Intern. Med.

How to diagnose rheumatoid arthritis early. A prediction model for persistent (erosive) arthritis

Arthritis Rheum.

Correlations between high-resolution computed tomography of the chest and clinical function in patients with rheumatoid arthritis. Prospective study in 75 patients

Joint Bone Spine