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P. Dewint, I. E. A. Hoffman, S. Rogge, R. Joos, A. Union, J. Dehoorne, J. Delanghe, E. M. Veys, F. De Keyser, D. Elewaut, Effect of age on prevalence of anticitrullinated protein/peptide antibodies in polyarticular juvenile idiopathic arthritis, Rheumatology, Volume 45, Issue 2, February 2006, Pages 204–208, https://doi.org/10.1093/rheumatology/kei133
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Abstract
Objectives. Anticitrullinated protein/peptide antibodies (ACPA) have an excellent diagnostic performance for rheumatoid arthritis (RA). Despite similarities between RA and polyarticular juvenile idiopathic arthritis (JIA), the prevalence of ACPA in polyarticular JIA is low. We wanted to evaluate the influence of age, disease duration and total immunoglobulin G (IgG) concentration on ACPA positivity in this cohort.
Methods. Patients with JIA were classified according to age and International League of Associations for Rheumatology classification. Sixty-one JIA patients aged less than 16 yr were included and classified as polyarticular JIA (poly JIA <16; n=23) or non-polyarticular JIA (n=38). In addition, a group of 21 polyarticular JIA patients, aged more than 16 yr (poly JIA >16) and a group of 51 RA patients were included. Antibodies to the synthetic citrullinated peptides pepA and pepB were detected by line immunoassay and antibodies to cyclic citrullinated peptides (CCP2) by enzyme-linked immunosorbent assay. Serum IgG was measured by fixed-time immunonephelometry.
Results. No ACPA reactivity was observed in the non-polyarticular group. In poly JIA <16, only 1/23 had anti-CCP2 antibody, whereas in poly JIA >16 patients a significantly higher fraction was detected (6/21). All but one of the anti-CCP2 reactive patients were rheumatoid factor (RF) positive. Assessing anti-CCP2 antibody concentration as a continuous variable, significantly higher titres were found in poly JIA >16 compared with poly JIA <16. No correlation between anti-CCP2 concentration and total IgG was detected. Four patients demonstrated immunoreactivity against pepA and pepB; all of them were anti-CCP2 reactive, poly JIA >16 patients.
Conclusions. ACPA are present in low prevalence in polyarticular JIA and are particularly found in the RF-positive subset. With age, a significant increase in anti-CCP2 positivity is observed in polyarticular JIA patients.
Substantial progress has recently been made in the field of serological markers for rheumatoid arthritis (RA). The promising diagnostic performance of antiperinuclear factor (APF), antikeratin antibodies and antifilaggrin antibodies has initiated the development of a range of new assays based on synthetic citrullinated peptides. This eventually resulted in the development of the second-generation anticyclic citrullinated peptide (CCP) enzyme-linked immunosorbent assay (CCP2 ELISA), characterized by remarkably good diagnostic properties with sensitivities ranging from 65 to 80% and specificities varying between 89 and 98.5% [1–4].
Furthermore a line immunoassay (LIA) was developed for the detection of antibodies directed to peptide A (pepA) and peptide B (pepB). These are synthetic citrullinated peptides that have been synthesized based on epitope mapping of human natural filaggrin [5]. In an independent study, anti-pepA antibodies had a sensitivity of 63.3% while being 100% specific for RA, while anti-pepB antibodies had a sensitivity of 54.2% and a specificity of 99.3% [1].
In juvenile idiopathic arthritis (JIA), the prevalence of these RA-associated antibodies varies across different studies. It has been reported that antikeratin antibodies can be found in up to 55% of patients with severe JIA [6], but the reported frequency of APF positivity is lower. One study found APF in fewer than 2% of JIA patients [7], while a second study found APF in 34% of patients [8]. Few studies about the prevalence of anti-CCP in JIA have been published. Avcin et al. [9] found 2% of JIA patients to be positive for anti-CCP antibodies. This is in accordance with Hromadnikova et al. [10], who reported anti-CCP positivity in 5% of JIA patients. Van Rossum et al. [11] found anti-CCP positivity in 15% of JIA patients; the majority of the anti-CCP positive patients had polyarticular disease and were rheumatoid factor (RF) positive.
It is striking that anti-CCP antibodies are preferentially found in polyarticular RF-positive JIA patients and not in polyarticular RF-negative patients or in JIA patients with other subtypes. Given the evident phenotypical similarities between polyarticular patients, irrespective of the presence of RF, one can hypothesize that the same pathophysiological mechanisms operate in these patients. The precise reasons for the absence of RF and the low prevalence of anti-CCP reactivity in polyarticular JIA, however, remain unclear. Several studies have indicated that immunoglobulin (Ig) titres in children steadily increase with age, suggesting that maturation of the humoral immune system is a rather slow process [12]. This age-dependent increase of immunoglobulins is apparent in all subclasses, albeit most prominent in the IgG2 subclass [13]. These observations suggest that the low anti-CCP titres in polyarticular JIA patients may reflect lower Ig titres. To test this we compared anticitrullinated protein/peptide antibodies (ACPA) in polyarticular JIA patients in relation to age and determined global IgG titres.
Methods
Patients
Arthritis was defined to be of juvenile onset if symptoms started before a child had reached the age of 16 yr. A patient with JIA was designated as JIA >16 if the studied sample was drawn after the patient's 16th birthday. Because the initial manifestations of disease activity could not always be unequivocally determined in the JIA population older than 16 yr, we classified these patients as polyarticular or as non-polyarticular. Only in the group of JIA patients aged less than 16 yr further classification according to the International League of Associations for Rheumatology (ILAR) classification was performed [14]. We obtained the following groups:
Polyarticular JIA younger than 16 yr (hereafter referred to as poly JIA <16) (n = 23); two of whom could be classified as RF-positive polyarticular JIA, 10 had RF-negative polyarticular JIA, eight patients had an extended oligoarthritis and three patients had become polyarticular after evolution from a systemic onset.
Non-polyarticular JIA younger than 16 yr (n = 38).
Polyarticular JIA older than 16 yr (hereafter referred to as poly JIA >16) (n = 21), six of whom were RF positive.
Adult patients with RA (n = 51).
All patients were followed at the Department of Rheumatology, University Hospital Ghent. The patient group poly JIA <16 consisted of patients whose serum samples were sent to the laboratory of the Department of Rheumatology (Ghent University Hospital) for routine work-up. Spare serum was available in 61 patients. The other two patient cohorts, poly JIA >16 and RA patients, consisted of all poly JIA >16 patients and random selection of 51 RA patients in continuous follow-up at the Department of Rheumatology; therefore they were representative of the specified patient population. Serum was obtained after clotting through centrifugation and was collected after routine work-up and frozen at –20°C. Serum samples were analysed retrospectively. The study and the collection of sera were approved by the local ethical committee.
Detection of anti-CCP antibodies
All sera were tested for anti-CCP antibodies by an ELISA using synthetic citrullinated peptides (Immunoscan RA, mark 2, Eurodiagnostica, Arnhem, The Netherlands). The ELISA was performed according to the manufacturer's instructions, including the use of a cut-off value of 25 U/ml.
Detection of anti-pepA and anti-pepB antibodies by line immunoassay (LIA)
The sera of poly JIA <16, poly JIA >16 and RA patients were also tested with an alternative ACPA assay: anti-pepA and anti-pepB antibodies were detected by a research LIA containing these two citrulline-containing peptides as described earlier (INNO-LIA™RA, Innogenetics, Ghent, Belgium) [5]. During each test run, a reference cut-off control sample was included, providing a cut-off intensity for each antigen line. Air-dried strips were read visually.
Measurement of total IgG titres
Serum samples from all JIA patients were analysed for IgG titres by fixed-time immunonephelometry on a BN II analyser (Dade Behring, Marburg, Germany) [15]. The assay was calibrated against the International CRM 470 reference material [16].
Statistical analysis
Frequencies were compared using the χ2 test or the Fisher exact test as appropriate. Anti-CCP antibody titres were compared using the Mann–Whitney test. Spearman's rho test was used to establish correlations between different parameters.
Results
One hundred and thirty-three patients were included in this study of whom 82 were JIA patients and 51 were RA patients. Detailed patient and disease characteristics at the time of serum collection are shown in Table 1.
. | Number of patients . | Age (yr) [median (range)] . | Sex ratio [F/M] . | Disease duration (yr) [median (range)] . |
---|---|---|---|---|
Non-polyarticular JIA | 38 | 9 (1–15) | 22/16 | 1.1 (0–10.0) |
Persistent oligoarthritis | 24 | 8 (1–14) | 18/6 | 0.8 (0–9.3) |
Systemic onset | 5 | 9 (4–11) | 1/4 | 2.2 (0.1–10.0) |
Enthesitis-related arthritis | 5 | 10 (2–15) | 1/4 | 0.1 (0–5.7) |
Psoriatic arthritis | 4 | 11 (8–14) | 2/2 | 4.3 (3.9–5.2) |
Poly JIA <16 | 23 | 10.5 (3–15) | 18/5 | 1.3 (0–7.5) |
Polyarticular onset (RF+) | 2 | 11.5 (11–12) | 2/0 | 1.7 (0–3.4) |
Polyarticular onset (RF–) | 10 | 10 (4–14) | 7/3 | 0.2 (0–3.3) |
Systemic onset | 3 | 15 (12–15) | 2/1 | 4.9 (3.3–6.7) |
Extended oligoarthritis | 8 | 10 (3–15) | 7/1 | 1.8 (0–7.5) |
Poly JIA >16 | 21 | 27 (16–52) | 17/4 | 21 (1.8–44) |
RA | 51 | 60 (30–79) | 40/11 | 10 (4–37) |
. | Number of patients . | Age (yr) [median (range)] . | Sex ratio [F/M] . | Disease duration (yr) [median (range)] . |
---|---|---|---|---|
Non-polyarticular JIA | 38 | 9 (1–15) | 22/16 | 1.1 (0–10.0) |
Persistent oligoarthritis | 24 | 8 (1–14) | 18/6 | 0.8 (0–9.3) |
Systemic onset | 5 | 9 (4–11) | 1/4 | 2.2 (0.1–10.0) |
Enthesitis-related arthritis | 5 | 10 (2–15) | 1/4 | 0.1 (0–5.7) |
Psoriatic arthritis | 4 | 11 (8–14) | 2/2 | 4.3 (3.9–5.2) |
Poly JIA <16 | 23 | 10.5 (3–15) | 18/5 | 1.3 (0–7.5) |
Polyarticular onset (RF+) | 2 | 11.5 (11–12) | 2/0 | 1.7 (0–3.4) |
Polyarticular onset (RF–) | 10 | 10 (4–14) | 7/3 | 0.2 (0–3.3) |
Systemic onset | 3 | 15 (12–15) | 2/1 | 4.9 (3.3–6.7) |
Extended oligoarthritis | 8 | 10 (3–15) | 7/1 | 1.8 (0–7.5) |
Poly JIA >16 | 21 | 27 (16–52) | 17/4 | 21 (1.8–44) |
RA | 51 | 60 (30–79) | 40/11 | 10 (4–37) |
. | Number of patients . | Age (yr) [median (range)] . | Sex ratio [F/M] . | Disease duration (yr) [median (range)] . |
---|---|---|---|---|
Non-polyarticular JIA | 38 | 9 (1–15) | 22/16 | 1.1 (0–10.0) |
Persistent oligoarthritis | 24 | 8 (1–14) | 18/6 | 0.8 (0–9.3) |
Systemic onset | 5 | 9 (4–11) | 1/4 | 2.2 (0.1–10.0) |
Enthesitis-related arthritis | 5 | 10 (2–15) | 1/4 | 0.1 (0–5.7) |
Psoriatic arthritis | 4 | 11 (8–14) | 2/2 | 4.3 (3.9–5.2) |
Poly JIA <16 | 23 | 10.5 (3–15) | 18/5 | 1.3 (0–7.5) |
Polyarticular onset (RF+) | 2 | 11.5 (11–12) | 2/0 | 1.7 (0–3.4) |
Polyarticular onset (RF–) | 10 | 10 (4–14) | 7/3 | 0.2 (0–3.3) |
Systemic onset | 3 | 15 (12–15) | 2/1 | 4.9 (3.3–6.7) |
Extended oligoarthritis | 8 | 10 (3–15) | 7/1 | 1.8 (0–7.5) |
Poly JIA >16 | 21 | 27 (16–52) | 17/4 | 21 (1.8–44) |
RA | 51 | 60 (30–79) | 40/11 | 10 (4–37) |
. | Number of patients . | Age (yr) [median (range)] . | Sex ratio [F/M] . | Disease duration (yr) [median (range)] . |
---|---|---|---|---|
Non-polyarticular JIA | 38 | 9 (1–15) | 22/16 | 1.1 (0–10.0) |
Persistent oligoarthritis | 24 | 8 (1–14) | 18/6 | 0.8 (0–9.3) |
Systemic onset | 5 | 9 (4–11) | 1/4 | 2.2 (0.1–10.0) |
Enthesitis-related arthritis | 5 | 10 (2–15) | 1/4 | 0.1 (0–5.7) |
Psoriatic arthritis | 4 | 11 (8–14) | 2/2 | 4.3 (3.9–5.2) |
Poly JIA <16 | 23 | 10.5 (3–15) | 18/5 | 1.3 (0–7.5) |
Polyarticular onset (RF+) | 2 | 11.5 (11–12) | 2/0 | 1.7 (0–3.4) |
Polyarticular onset (RF–) | 10 | 10 (4–14) | 7/3 | 0.2 (0–3.3) |
Systemic onset | 3 | 15 (12–15) | 2/1 | 4.9 (3.3–6.7) |
Extended oligoarthritis | 8 | 10 (3–15) | 7/1 | 1.8 (0–7.5) |
Poly JIA >16 | 21 | 27 (16–52) | 17/4 | 21 (1.8–44) |
RA | 51 | 60 (30–79) | 40/11 | 10 (4–37) |
Anti-CCP2 antibodies
No positivity for anti-CCP2 antibodies was seen in the non-polyarticular JIA group (Table 2). In poly JIA <16 patients, only 1/23 (4.3%) had anti-CCP2 antibodies. However, in the group of poly JIA >16 patients a significantly higher fraction of patients, 6/21 (28.6%), was positive for anti-CCP2 antibodies (P = 0.042, Fisher exact test). By contrast, considering the RF-positive subset in childhood and poly JIA >16 patients, anti-CCP2 antibodies were detected in one out of two (50%) and five out of seven (71%) patients, respectively. In the group of RA patients, anti-CCP2 antibodies were found in 68.6%. Anti-CCP2 antibodies were significantly more prevalent in adult RA compared with polyarticular JIA, whether they had reached the age of 16 or not (both P<0.001, Fisher exact test).
. | . | Anti-CCP2 positivity . | . | Anti-CCP2 negativity . | . | . | . | ||
---|---|---|---|---|---|---|---|---|---|
Group . | Number of patients . | Anti-CCP2+ [n (%)] . | ELISA value (U/ml) [median (range)] . | Anti-CCP2– [n] . | ELISA value (U/ml) [median (range)] . | Anti-pepA+ [n (%)] . | Anti-pepB+ [n (%)] . | ||
Non-polyarticular JIA | 38 | 0 (0) | – | 45 | 2 (1–6) | 0 | 0 | ||
Poly JIA <16 | 23 | 1 (4.3) | 54 | 22 | 1 (0–4) | 0 | 0 | ||
Poly JIA >16 | 21 | 6 (28.6) | 357 (27–1600) | 15 | 2 (1–10) | 4 (19.0) | 4 (19.0) | ||
RA | 51 | 35 (68.6) | 301 (42–1600) | 16 | 7 (4–20) | 26 (51.0) | 24 (47.1) |
. | . | Anti-CCP2 positivity . | . | Anti-CCP2 negativity . | . | . | . | ||
---|---|---|---|---|---|---|---|---|---|
Group . | Number of patients . | Anti-CCP2+ [n (%)] . | ELISA value (U/ml) [median (range)] . | Anti-CCP2– [n] . | ELISA value (U/ml) [median (range)] . | Anti-pepA+ [n (%)] . | Anti-pepB+ [n (%)] . | ||
Non-polyarticular JIA | 38 | 0 (0) | – | 45 | 2 (1–6) | 0 | 0 | ||
Poly JIA <16 | 23 | 1 (4.3) | 54 | 22 | 1 (0–4) | 0 | 0 | ||
Poly JIA >16 | 21 | 6 (28.6) | 357 (27–1600) | 15 | 2 (1–10) | 4 (19.0) | 4 (19.0) | ||
RA | 51 | 35 (68.6) | 301 (42–1600) | 16 | 7 (4–20) | 26 (51.0) | 24 (47.1) |
. | . | Anti-CCP2 positivity . | . | Anti-CCP2 negativity . | . | . | . | ||
---|---|---|---|---|---|---|---|---|---|
Group . | Number of patients . | Anti-CCP2+ [n (%)] . | ELISA value (U/ml) [median (range)] . | Anti-CCP2– [n] . | ELISA value (U/ml) [median (range)] . | Anti-pepA+ [n (%)] . | Anti-pepB+ [n (%)] . | ||
Non-polyarticular JIA | 38 | 0 (0) | – | 45 | 2 (1–6) | 0 | 0 | ||
Poly JIA <16 | 23 | 1 (4.3) | 54 | 22 | 1 (0–4) | 0 | 0 | ||
Poly JIA >16 | 21 | 6 (28.6) | 357 (27–1600) | 15 | 2 (1–10) | 4 (19.0) | 4 (19.0) | ||
RA | 51 | 35 (68.6) | 301 (42–1600) | 16 | 7 (4–20) | 26 (51.0) | 24 (47.1) |
. | . | Anti-CCP2 positivity . | . | Anti-CCP2 negativity . | . | . | . | ||
---|---|---|---|---|---|---|---|---|---|
Group . | Number of patients . | Anti-CCP2+ [n (%)] . | ELISA value (U/ml) [median (range)] . | Anti-CCP2– [n] . | ELISA value (U/ml) [median (range)] . | Anti-pepA+ [n (%)] . | Anti-pepB+ [n (%)] . | ||
Non-polyarticular JIA | 38 | 0 (0) | – | 45 | 2 (1–6) | 0 | 0 | ||
Poly JIA <16 | 23 | 1 (4.3) | 54 | 22 | 1 (0–4) | 0 | 0 | ||
Poly JIA >16 | 21 | 6 (28.6) | 357 (27–1600) | 15 | 2 (1–10) | 4 (19.0) | 4 (19.0) | ||
RA | 51 | 35 (68.6) | 301 (42–1600) | 16 | 7 (4–20) | 26 (51.0) | 24 (47.1) |
We also determined the anti-CCP2 antibody concentration as a continuous variable and, as demonstrated in Fig. 1, titres were significantly higher in RA patients than in all other groups (all P<0.001, Mann–Whitney test). Poly JIA >16 patients had higher titres than poly JIA <16 patients (P = 0.005, Mann–Whitney test) or non-polyarticular JIA (P = 0.043, Mann–Whitney test). Only in the poly JIA >16 patients a weak but significant correlation was detected between disease duration and anti-CCP2 titres (ρ = 0.547, P = 0.043 Spearman's rho).
Anti-pepA and anti-pepB antibodies
No positive results were found in childhood JIA patients. In the poly JIA >16 patients, anti-pepA and anti-pepB antibodies were detected in four patients (19.0%), all of whom were also positive for anti-CCP2 antibodies. On the other hand, in the RA group, two anti-CCP2-negative patients were found to be positive for anti-pepA. No positive results for anti-pepB could be detected in the anti-CCP2-negative group. In RA patients anti-pepA antibodies were present in 26/51 patients (51.0%) and anti-pepB antibodies in 24/51 (47.1%). Anti-pepA and anti-pepB antibodies were significantly more frequent in RA compared with poly JIA >16 (P = 0.012 and P = 0.027, respectively, Fisher exact test) and poly JIA <16 (P<0.001 and P<0.001, Fisher exact test). A trend to a higher prevalence of anti-pepA and anti-pepB antibodies was seen in poly JIA >16 compared with poly JIA <16 (P = 0.107, Fisher exact test).
Total IgG titres
IgG titres were determined in the three different JIA groups (Fig. 2). Serum IgG titres were significantly higher than the reference values (P<0.001, one-sample t-test). The Kruskal–Wallis test indicated that no significant differences existed between the different subgroups. Furthermore, Spearman's rho analysis could not detect a correlation between anti-CCP2 and IgG titres.
Discussion
ACPA are well established as serological markers for the diagnosis of RA with high sensitivity and remarkably high specificity [5, 17, 18]. In the present study, we determined the significance of ACPA in the diagnosis of polyarticular JIA in relation to age. Previous studies have reported that anti-CCP antibodies can be found in JIA patients, albeit at low prevalence. Moreover, virtually all positivity for anti-CCP antibodies is seen in RF-positive polyarticular patients [3, 11, 19]. Nevertheless, the majority of polyarticular JIA patients are RF negative and have striking phenotypical similarities with the RF-positive subset. It is known that B-cell maturation in children is a slow process. The impact of age on development of autoantibodies is poorly studied so far and we therefore hypothesized that the low prevalence of ACPA in polyarticular JIA patients may reflect lower Ig production, as is known for healthy individuals [12, 13].
Recently, several reports have appeared on anti-CCP2 reactivity in JIA. The results from Avcin et al. [9], in which a low prevalence of 2% was found, are consistent with the results presented here. By contrast, Low et al. [19] reported a much higher prevalence, which may be caused by several methodological differences. Another confounding factor was the high prevalence of RF-positive patients within their study, suggesting a particular bias in patient selection, which could account for the high prevalence of ACPA. This is consistent with our results in which anti-CCP2 reactivity was particularly present in RF-positive patients.
Positivity for ACPA was primarily found in the polyarticular subset of JIA patients, and especially in poly JIA >16. The prevalence of anti-CCP2 antibodies was significantly higher in poly JIA >16 patients. In addition, the anti-CCP2 titres were significantly higher in the poly JIA >16 group compared with poly JIA <16. Similar observations were made for anti-pepA and anti-pepB reactivity. This observation may reflect age-dependent B-cell maturation, or alternatively it may be a reflection of disease duration. We consider the latter hypothesis rather unlikely because of the weak correlation observed between anti-CCP2 titres and disease duration in poly JIA >16 patients. Moreover, this correlation was not detected in the RA population nor within the poly JIA <16 cohort. To examine the contribution of the humoral immune system to the increase of anti-CCP2 titres with age, total IgG titres were determined. IgG subclasses were not determined merely because previous studies indicated that anti-CCP antibodies found in RA patients are mainly of the IgG class, polyclonally distributed over the different subclasses, with a predominance of IgG1 [20]. Serum IgG titres were significantly higher than the reference values, as would be expected in autoimmune disease. However, the total IgG titres did not differ between the different groups, nor could a correlation be detected between total IgG and anti-CCP2 titres, indicating that positivity for anti-CCP2 is not influenced by total IgG titres.
The observation that RF positivity in JIA is associated with a higher probability of anti-CCP positivity may lead to the speculation that the presence of anti-CCP2 antibodies is dependent on RF positivity rather than upon age. Although we cannot formally exclude this possibility, it should be noted that in addition to the frequency of positivity, the anti-CCP2 titres were also correlated with age in the poly JIA group. Nevertheless, prospective follow-up studies in RF-negative polyarticular JIA patients will be required to evaluate the natural course of occurrence of ACPA and RF with age.
In conclusion, our data show a low prevalence of ACPA in JIA, with presence primarily in the RF-positive polyarticular subset. In addition, to our knowledge, our group is the first to provide evidence that anti-CCP reactivity in polyarticular JIA patients correlates with age. The precise mechanisms, however, remain to be investigated.
We would like to thank Mrs V. Baert, Mrs J. Discart, Mrs H. Lootens and Mrs A. Heirwegh for their excellent technical support. We would also like to express our appreciation to Mrs A. De Vreese for administrative help.
This work was supported by grants of the Fund for Scientific Rheumatology Research Council of Ghent University. Pieter Dewint is an aspirant of the Fund for Scientific Research Flanders.
A. Union is an employee of Innogenetics NV. The other authors declare no conflicts of interest.
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Author notes
1Departments of Rheumatology and 2Clinical Chemistry and 3Department of Paediatrics, Center for Paediatric Rheumatology, Ghent University Hospital and 4Innogenetics NV, Ghent, Belgium.
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