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The clinical value of serum anti-cyclic citrullinated peptide antibodies for juvenile idiopathic arthritis / Serum antisiklik sitruline peptid antikorlarinin jvenil diyopatik artrit acisindan klinik degeri.

Juvenile idiopathic arthritis (JIA) is a common systemic rheumatic disease among children. Its dominant feature is chronic synovitis accompanied by different degrees of involvement of other organs, but it does not affect bones and joints. Juvenile idiopathic arthritis is an autoimmune disease which causes the highest disability rate among children, yet its etiology still remains unknown.(1) It can be classified into different subtypes, such as systemic JIA, polyarticular JIA, and oligoarticular JIA, according to its onset characteristics and early six-month course. (2) Rheumatoid arthritis (RA) is one of the most common autoimmune diseases among adults, with an incidence rate of 1-2%. (3) Although rheumatoid factor (RF) is one of the serological markers of RA, neither its sensitivity nor its specificity in diagnosis of JIA is high (4), (5) since its positive expression can only be detected by latex agglutination in 5-10% of children with JIA. For example, among children with polyarticular JIA, positive RF can only be detected in those with a late disease onset and in those whose joints are severely destructed. (2) At present, the diagnosis of JIA primarily depends on the clinical and radiological manifestations of JIA due to the lack of a specific and sensitive serological marker. Anti-cyclic citrullinated peptide (anti-CCP) antibodies have only been recently discovered to have a diagnostic value for RA, with a specificity of 96-100% (6) and a sensitivity of 40-85%. (7), (8) However, their diagnostic value for JIA is still controversial. Some scholars have reported that their sensitivity in the diagnosis of JIA was 4.4-15%, (9), (10) but others have determined that it was 16.7-30.0%, (11), (12) or even as high as 58.5%. (13) An early diagnosis of JIA along with drug intervention treatment that occurs as early as possible can better control the disease's progression, relieve joint destruction, and improve a patient's prognosis.

In our study, the serum anti-CCP antibodies in children with JIA and patients with RA were detected using enzyme-linked immunosorbent assays (ELISA), and these were then compared. This data combined with the clinical and radiological data were analyzed to explore the diagnostic value of anti-CCP antibodies for JIA.

PATIENTS AND METHODS

Subjects

The JIA group was comprised of children diagnosed with JIA at the Capital Institute of Pediatrics between February 2009 and December 2009. The RA group was made up of adults diagnosed with RA during the same period, and the control group was composed of healthy children who received physical examinations during this time period.

Juvenile idiopathic arthritis was diagnosed according to the classification system that was amended by the International League of Associations for Rheumatology (ILAR) in 2001, (2) and RA was diagnosed according to the classification system developed by the American College of Rheumatology (ACR) in 1987. (14)

Clinical and radiological data

A total of 72 children (33 boys, 39 girls; mean age 7.6[+ or -]3.9 years; range 2 to 15.9 years) with JIA were involved in our study. Their courses of JIA ranged from six to 120 months. Among the children, 29 suffered from systemic JIA, 27 had oligoarticular JIA, and 16 had been diagnosed with polyarticular JIA. The RA group contained 65 patients 14 males and 51 females; mean age of 47[+ or -]14.3 years; range 17 to 75 years, and the control group featured 22 children (10 boys, 12 girls; mean age 14.1[+ or -]0.4 years; range 6.1 to 15.7 years) (Table 1).
Table 1. Demographic data of the subjects

                               Cases  Male to female ratio

Juvenile idiopathic arthritis     72                 39:33

  Polyarticular                   16

  Oligoarticular                  27

  Systemic                        29

Rheumatoid arthritis              65                 14:51

Control                           22                 21:10

                                       Age
                                 Mean[+ or -]SD

Juvenile idiopathic arthritis    7.58[+ or -]3.93

  Polyarticular

  Oligoarticular

  Systemic

Rheumatoid arthritis           47.38[+ or -]14.28

Control                          14.1[+ or -]0.38

SD: Standard deviation.


In the RA group, the average disease course was 14.06 months (ranging from three to 120 months). Positive RF was detected in 11 of the patients, and imaging showed that joint involvement occurred in seven cases, including five with bone destruction and two with cervical joint dislocation.

Blood sample collection

Two milliliters of peripheral venous blood was extracted from the empty stomachs of the participants in the morning. After centrifugation, the serum was kept in a refrigerator at -20[degrees] C, and the samples were not thawed until analysis.

Anti-CCP antibody detection

The ELISA method was used to test the anti-CCP antibodies, and the procedures were performed according to the instructions indicated in the kits that were utilized (Axis-Shield, Diagnostics Limited, Dundee, Scotland; Euroimmun, Lubeck, Germany; and Shanghai Fuchun Jianye (group) Limited Company, Shanghai, China). The results were obtained based on the standard curves for determination of positivity or negativity of the serum samples.

Clinical data collection

The clinical data of the patients with JIA, including the course of the disease, symptoms, vital signs, and laboratory examination indices such as RF and radiologic data, was carefully collected, Statistical analysis.

The data was analyzed using the Statistical Package for Social Sciences (SPSS Inc., Chicago, Illinois, USA) version 13.0 software program for Windows. Statistical descriptions were given to the measurement data, Student's t-test was used for comparisons between sample means, and a chi-square test was carried out for enumeration data. A p value of <0.05 was considered statistically significant.

RESULTS

Comparisons among different groups

The anti-CCP antibodies in the different groups were detected using the Axis-Shield kit. The results showed that positive anti-CCP antibodies were detected in nine children with JIA (12.5%) and 46 adults with RA (73.85%), whereas no positive anti-CCP antibodies were detected in the control group. The chi-square test showed significant differences in the positive anti-CCP antibody rate among the three groups (p<0.001; Figure 1).
Healthy children   0/22

JIA Groups         9/72

RA                46/65

Note: [x.sup.2]= 107.3, p<0.001

Figure 1. The positive anti-cyclic citrullinated peptide
antibody rates of the control, juvenile idiopathic arthritis
(JIA), and rheumatoid arthritis (RA) groups. CCP: Cyclic
citrullinated peptide.

Note: Table made from bar graph.


Comparisons among different JIA subgroups

In the JIA group, positive anti-CCP antibodies were found in five children with polyarticular JIA (31.25%) and four children with oligoarticular JIA (14.8%), but no positive anti-CCP antibodies were found in the systemic group. The chi-square test showed that both the polyarticular group and the oligoarticular group had a significant difference in the positive anti-CCP antibody rate compared with the systemic group (p<0.001; Figure 2).
Polyarticular          5/16

Oligoarticular Groups  4/27

Systemic               0/29

Note: [c.sup.2]= 107.3, p<0.001

Figure 2. The positive anti-cyclic citrullinated peptide
antibody rates of different juvenile idiopathic arthritis
subtypes. CCP: Cyclic citrullinated peptide.

Note: Table made from bar graph.


Comparisons between the positive and negative anti-CCP antibody JIA groups

Rheumatoid factor (RF), radiological changes, and disease courses were compared between the positive and negative anti-CCP antibody JIA groups (Table 2). Among the nine children with positive anti-CCP antibodies, six were found to have positive RF, and three had joint lesions. Among the 63 children with negative anti-CCP antibodies, five were found to have positive RF, and four had joint lesions. These two groups showed significant differences in both the positive RF rate and joint lesions according to the chi-square tests (p<0.001). However, no significant difference in the mean disease course was found between the two JIA groups.
Table 2. Comparisons between rheumatoid factor, radiological
changes, and disease course in the positive and negative
anti-cyclic citrullinated peptide antibody juvenile idiopathic
arthritis groups

              Positive  JIA   Negative  JIA  Chi-square

                  n      %         n     %

Rheumatoid         6/9  66.7      5/63  7.9     118.778
factor
positive
rate

Radiological       3/9  33.3      4/63  6.3     124.778
changes

Disease           18.1            13.7          0.606 *
course
(months)

                  p

Rheumatoid    <0.001
factor
positive
rate

Radiological  <0.001
changes

Disease        0.546
course
(months)

Anti-CCP: Anti-cyclic citrullinated peptide; JIA: Juvenile
idiopathic arthritis; * a t value between the two sample
means.


Comparisons in the polyarticular and oligoarticular JIA groups

In both the polyarticular JIA group and the oligoarticular JIA group, disease courses were compared between children with positive and negative anti-CCP antibodies (Table 3). Among the 16 children with polyarticular JIA, five were identified with positive anti-CCP antibodies, and 11 were found to have negative anti-CCP antibodies. The mean disease course of the positive group was 13.2 months (ranging from 3 to 24 months) while it was 23.12 months (ranging from 3 days to 60 months) for the negative group. No significant difference was determined (t= -0.83, p=0.42). Among the 27 children with oligoarticular JIA, four were found to have positive anti-CCP antibodies. The mean disease course of the positive group was 23.0 months (ranging from 7 to 60 months) while it was 12.7 months (ranging from 2 days to 48 months) for the negative group. Again, there was no significant difference (t=1.21, p=0.47).
Table 3. Comparisons between the disease courses in both
the polyarticular juvenile idiopathic arthritis group and
the oligoarticular group

                   Disease        Disease       t      p
                course of the  course of the
                  positive       negative
                    group          group
                  (months)       (months)

Polyarticular      14.20[+ or     23.12[+ or  -0.83  0.42
                       -]9.93        -]22.67

Oligoarticular     23.00[+ or     12.71[+ or   1.21  0.47
                      -]24.80        -]14.02


Comparisons of the results obtained using different kits

The results obtained using different kits were also compared (Table 4). The positive anti-CCP antibody rates did not show a significant difference when the chi-square test was applied (p=0.86), and the consistency test also showed no significant difference (Kappa=0.884, p=0.08).
Table 4. Comparisons of the positive anti-cyclic citrullinated
peptide antibody rates of the patients with juvenile
idiopathic arthritis using different kits

               The           Chi-square    p     Kappa    p
             positive
               rate
                 n         %

Anti-CCP
antibodies

  Axis-shield    9/72  12.5

  Shanghai      11/72  15.3       0.301  0.86  0.884  0.08
  Fuchun

  Euroimmun     11/72  15.3

CCP: Cyclic citrullinated peptide.


DISCUSSION

Up to now, the factors that cause JIA and its pathogenesis still remain explored mystery. Juvenile idiopathic arthritis has clinical features which greatly differ from those of RA.[15,16] It is also generally thought to be a heterogeneous disease that has close correlations with genetic predisposition, immunologic derangement, and environmental factors. Based on differences in onset features, clinical manifestations, disease courses, and outcomes, JIA can be classified into different subtypes such as systemic JIA, polyarticular JIA, and oligoarticular JIA. (17) Juvenile idiopathic arthritis is an autoimmune disease which can lead to a high disability rate among children; therefore, early diagnosis and treatment are vital for the improvement of joint lesions and the prognosis of the patients.

However, since a highly specific and sensitive laboratory marker of JIA has not yet been found, diagnosis mainly depends on the clinical manifestations. Although RF has a high sensitivity in the diagnosis of RA (but with a low specificity), it has a low sensitivity in the diagnosis of JIA. (18) Anti-cyclic citrillunated peptide antibodies have only been recently reported to have specific antibodies which reveal a diagnostic value for the diagnosis of RA. (19) In the current study, the positive anti-CCP antibody rate in the JIA group was 12.5%, which is basically consistent with a previous report by van Rossum et al., (10) and the rate of the control group was 0%. These results suggest that anti-CCP antibodies have a high specificity in the diagnosis of JIA (100%). Among 65 patients with RA, 48 had positive anti-CCP antibodies, and the rate was 73.8%, which falls between the previously reported rates of 40% and 85% seen in the literature. (7), (8), (20) These results show that anti-CCP antibodies have a lower sensitivity to JIA than RA. Significant differences in distribution among patients with different subtypes of JIA have been determined via anti-CCP antibodies. In our study, the positive anti-CCP antibody rates of the polyarticular, oligoarticular, and systemic JIA groups were 45.5%, 17.4% and 0%, respectively. This suggests that they are of certain directive significance in JIA clinical typing.

In addition, in order to make sure that the results obtained from our experiment were stable, parallel detections were performed using three different types of kits, and no significant differences were detected among the positive rates of the experimental subjects. This suggests that ELISA is a stable and reliable method for serum anti-CCP antibody detection.

Furthermore, we also analyzed radiological data in our study, and the results showed that joint destruction in the positive anti-CCP antibody JIA group was more severe than that in the negative anti-CCP antibody JIA group. This suggests that anti-CCP antibody detection has an important role in the evaluation of the severity of joint destruction in patients with JIA and in the prognosis of the patients. In addition, the RF positive rate of the positive anti-CCP antibody group was noticeably higher than that of the negative group, suggesting that the combined detection of anti-CCP antibodies and RF is helpful for increasing the sensitivity and specificity in the diagnosis of JIA. These results are consistent with previous studies, (21-23) and their simultaneous presence may be an indication for earlier immunosuppressive treatment. (24)

No significant difference in disease course was found between the positive and negative anti-CCP patients in either the polyarticular group or the oligoarticular group, which seems to indicate that anti-CCP antibodies cannot serve as a reliable serological marker in the early diagnosis of JIA. However, our study showed that positive anti-CCP antibodies were primarily found in children with polyarticular and oligoarticular JIA, which conveys the idea that anti-CCP antibody detection might be of clinical significance in JIA typing and the prognostic evaluation of patients.

Declaration of conflicting interests

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding

This study was supported by the 11th Five-Year Plan of China (2008BAI59B02).

REFERENCES

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(2.) Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390-2.

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(9.) Brunner JK, Sitzmann FC. Anticyclic citrullinated peptide antibodies in juvenile idiopathic arthritis. Mod Rheumatol 2006;16:372-5.

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(11.) Kang M, Wang HW, Cheng PX, Yin ZD, Li XO, Shi H, et al. The clinical significance of anti-cyclic citrullinated peptide antibodies in juvenile idiopathic arthritis. Chinese Journal of Practical Pediatrics 2006; 21:446-8.

(12.) Kong LH, Peng S. Significance of Hidden Rheumatoid Factor IgM, Anti-cyclic citrullinated peptide antibodies, antikeratin antibodies, combined test in diagnosis of juvenile idiopathic arthritis. Journal of Applied Clinical Pediatrics 2007;22:680-1.

(13.) Teng Q, Liu YG, He XH. Diagnostic significance of combined testing of anti-cyclic citrullinated peptide antibody and hidden rheumatoid factor immunoglobulin M in patients with juvenile rheumatoid arthritis. Journal of Applied Clinical Pediatrics 2004;19:845-7.

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(18.) Lawrence JM 3rd, Moore TL, Osborn TG, Nesher G, Madson KL, Kinsella MB. Autoantibody studies in juvenile rheumatoid arthritis. Semin Arthritis Rheum 1993;22:265-74.

(19.) van Venrooij WJ, Zendman AJ, Pruijn GJ. Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. Autoimmun Rev 2006;6:37-41.

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(23.) van Jaarsveld CH, ter Borg EJ, Jacobs JW, Schellekens GA, Gmelig-Meyling FH, van Booma-Frankfort C, et al. The prognostic value of the antiperinuclear factor, anti-citrullinated peptide antibodies and rheumatoid factor in early rheumatoid arthritis. Clin Exp Rheumatol 1999;17:689-97.

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Turk J Rheumatol 2012;27(4):221-226 doi: 10.5606/tjr.2012.040

Xiaolan HUANG, (1) Zheng XU, (1) Fengqi WU, (2) Xiaodai CUI, (1) Xiaofeng LI, (3) Xianzi CONG, (3) Jianglin ZHANG (3)

(1.) Clinical Central Laboratory, Capital Institute of Pediatrics, Beijing, China;

(2.) Department of Rheumatology-Immunology, the Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China;

(3.) Department of Rheumatology, Hinese People's Liberation Army General Hospital, Beijing, China

Received: February 21, 2012 Accepted: May 19, 2012

Correspondence: Xiaodai Cui, M.D. Clinical Central Laboratory, Capital Institute of Pediatrics, 100020 Beijing, China. Tel: 86-010-85695548 e-mail: xiaodaicui@126.com
COPYRIGHT 2012 Turkish League Against Rheumatism
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2012 Gale, Cengage Learning. All rights reserved.

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Title Annotation:Original Article
Author:Huang, Xiaolan; Xu, Zheng; Wu, Fengqi; Cui, Xiaodai; Li, Xiaofeng; Cong, Xianzi; Zhang, Jianglin
Publication:Turkish Journal of Rheumatology
Article Type:Clinical report
Date:Dec 1, 2012
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