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*Corresponding author: E-mail: Mariajnad66@gmail.com; 
 
 
 

Asian Journal of Immunology 
 
3(1): 305-310, 2020; Article no.AJI.61363 
 

 
 

 

 

The Relationship between the Levels of Anti Cyclic 
Citrullinated Protein Antibodies Type2 (ACPA2) and 

the Severity of Erosive Rheumatoid Arthritis (RA) 
 

M. Jnad1*, K. Aldou1 and H. Yazaji2 

 
1
Division of Rheumatology, Department of Internal Medicine, Tishreen University Hospital,  

Lattakia, Syria. 
2
Department of Laboratory, Tishreen University Hospital, Lattakia, Syria. 

 
Authors’ contributions 

 
This work was carried out in collaboration among all authors. Author MJ designed the study, 

performed the statistical analysis, wrote the protocol and wrote the first draft of the manuscript, 
managed the analyses of the study and managed the literature searches. Author KA was supervisor 

professor. Author HY was assistant supervisor professor. All authors read and approved the final 
manuscript. 

 
Article Information 

 
Editor(s): 

(1) Dr. Wagner Loyola, Brazilian Agricultural Research Corporation, Brazil. 
Reviewers: 

(1) Ibrahim Mohamad Saeed Shnawa, University of Qasim, Iraq. 
(2) K. Ramya, Tamil Nadu Veterinary and Animal Sciences University, India. 

Complete Peer review History: http://www.sdiarticle4.com/review-history/61363 

 
 
 
 

Received 15 July 2020  
Accepted 20 September 2020 
Published 25 September 2020 

 
 
ABSTRACT 
 

Background: Rheumatoid arthritis (RA) is a chronic systemic disease, characterized by 
autoimmunity. One of the most specific and important diagnostic and prognostic markers of RA are 
antibodies, Anti Cyclic Citrullinated Protein Antibodies (ACPA). 
Objective: The purpose of this study was to investigate the association between ACPA (Anti-CCP) 
levels and radiological damage. 
Methods: An observational Cross-sectional study included 54 patients fulfilling the ACR-EULAR 
2010 criteria for RA, with minimum disease duration of 1 year. Radiographs were scored using a 
modified Sharp score (Van der Heijde modification of Sharp's score 1989). ACPA levels were 
determined using immunofluorescence assay. 
Results: ACPA levels were strongly associated with radiographic severity and there was a 
significant relationship between ACPA levels and total Sharp score (p=0.0001). 

Original Research Article 



 
 
 
 

Jnad et al.; AJI, 3(1): 305-310, 2020; Article no.AJI.61363 
 

 

 
306 

 

Conclusion: This study concluded that ACPA is an independent severity factor for RA, and our 

data supports the association between ACPA and radiographic severity.  
 

 
Keywords: Anti cyclic citrullinated protein; Type2 (ACPA2); rheumatoid arthritis; chronic systemic 

disease. 
 

ABBREVIATIONS  
 
RA  : Rheumatoid Arthritis 
ACPA  : Anti citrullinated  

  peptides antibody 
Anti-CCP : Anti Cyclic Citrullinated 

  Protein Antibodies 
ACR  : American College of 

  Rheumatology 
EULAR  : European League 

  Against Rheumatism 
RF  : Rheumatoid Factors 
DMARD : Disease modifying anti 

  rheumatic drugs 
 

1. INTRODUCTION 
 
Rheumatoid Arthritis (RA) is a chronic systemic 
disease of unknown origin, characterized by 
autoimmunity, with the presence of 
autoantibodies in the blood and joint fluid. One of 
them is ACPA, which state high disease 
specificity and may contribute to the pathological 
process of the disease such as erosiveness and 
synovitis [1]. 
 
If untreated, it usually leads to progressive joint 
damage and reduction of functional capacity and 
quality of life [2,3]. 
 
Early diagnosis and effective intervention may 
prevent joint damage, increase the possibility of 
achieving remission and improve the outcome 
[4]. 
 
Radiography is the most common method for 
evaluating the existence of structural damage, 
which results from cumulative disease activity, 
and determining the effectiveness of treatment 
by estimating bone erosions and joint space 
narrowing on conventional radiography [5]. 

 
ACPA positive patients are at particularly high 
risk for developing severe forms of RA and 
severe radiographic damage, as they are 
independent severity factor for Rheumatoid 
Arthritis (RA), and may be very useful biomarkers 
to predict disease damage [6,7]. There is no 
research on association between ACPA and 

structural damage in RA patients in Syria. The 
objective of the present work was to map the 
possible association betweenACPA2 and the 
radiographic severity of the RA patient joints. 

 
2. METHODS AND PATIENTS 
 
An observational cross-sectional study included 
patients (N=54; 45 female, 9 male) with RA 
(duration more than 1 year) fulfilling the ACR-
EULAR 2010 criteria for RA, at the department of 
Rheumatology, Tishreen University Hospital, 
Lattakia, Syria. Over 1year period from April 
2019 to March 2020, patients having an overlap 
of RA with other rheumatic disease like gout 
were excluded from the study. 
Radiographs of hand and feet were scored using 
a modified Sharp score (Van der Heijde 
modification of Sharp's score). 

 
2.1 Antibody Measurement (ACPA/Anti 

CCP) 
 
Anti CCP were measured, in a blind fashion, at 
the Immunological laboratory in Tishreen 
Hospital using an (i-chromα Anti-CCP Plus) kit 
based on the immunofluorescence assay 
method. A value of > 5.0 U/ml was considered 
positive as per the manufacturers' 
recommendations. 

 
RF was measured using the standard latex 
agglutination technique. 

 
2.2 Measure of Disease Outcome 

(Structural Damage) 
 
The radiographs were evaluated by two senior 
rheumatologists in a blind fashion regarding 
serology and clinical status, with high 
concordance between them. 

 
Posterior - anterior radiographs of the hands, 
wrists, and feet were obtained and were 
examined blind by a two rheumatologists, and 
graded according to modified Sharp score (Van 
der Heijde modification of Sharp's score) in 
comparison with standard reference films. 



 
 
 
 

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307 

 

The scoring system included erosion score: 16 
locations in each hand and wrist, and 12 location 
in each foot were scored. Each location in the 
hand/wrist and foot was scored individually using 
a 6-point scale from 0 to 5 based on the number 
and size of discrete erosions in each location. 

 
Joint space narrowing (JSN) score: 15 locations 
in each hand and wrist, and 6 locations in each 
foot were scored using a 5-point scale (from 0 to 
4). 

 
The maximum erosion score is 160 for hands 
and wrists, and 120 for feet. The maximum JNS 
score is 120 for hands and wrists, and 48 for 
feet. The total score ranges from 0 to 448 [8]. 

 
2.3 Statistics 
 
All data were analyzed using the Statistical 
Package for Social Sciences (SPSS, Version 
20). Data were presented in simple measures of 
frequency, percentage, mean, and standard 
deviation. 

 
Non-parametric test Mann Whitney used for non-
normally distributed data, while correlation 
between quantitative data were tested using 
Person Correlation. Results were considered 
statistically significant with a p-value<5%. 
 

 
 

Fig. 1. Distribution of patients according to 
sex 

3. RESULTS 
 

The cross-sectional study includes 54 patients 
(45 female, 9 male) with RA, the median (IQR, 
Interquartile range) age was 50.5 (27-80) yr. The 

median (IQR, Interquartile range) disease 
duration was 2.7 year (1-20) yr, the proportion of 
females in the study was 83.3%. 94.4% of the 
patients were treated with DMARDs. About 68.5 
per cent (n=38) patients were seropositive 
(positive for RF), and 81.5 per cent (n=44) 
patients had erosive disease. 
 

On bivariate analysis, patients with erosive 
disease had a significantly higher disease 
duration, DMARD naïve period, RF positivity and 
ACPA titers than patients with non-erosive 
disease (Table 1). 
 

3.1 Association among Radiographic 
Outcome and Anti-CCP2 (ACPA) 
Status 

 

In our study ACPA titers were strongly 
associated with radiographic severity as 
measured using Sharp van der Heijde score (p-
value=0.0001). 
 

4. DISCUSSION 
 

 We founded that disease duration, 
DMARD naïve period, RF titers, and ACPA 
titers were significantly higher in patients 
with erosive disease compared with non-
erosive disease (Table 1). The most 
significant and important factor of them all 
was ACPA titers (p=0.001). This result 
compatible with the study that was done by 
Shankar et al [9]. 

 The long duration without compatible 
treatment with DMARDs can be attributed 
in Syria to the lack of medications in the 
light of the economic situation. 

 The most significant difference was in 
ACPA, RF titers between patients with 
erosive and non-erosive disease, what 
confirms that the combination of ACPA and 
RF are associated with more aggressive 
articular disease and that the association 
of both RF and ACPA is independent 
factor for more severe destructive disease 
[10,1,6]. 

 The high positive correlation between 
ACPA titers and Sharp scores (r=0.7, 
p=0.0001) (Fig. 2) indicates that ACPA has 
a significant role in predicting the 
radiographic and structural damage in 
rheumatoid patients, and that corresponds 
with a previous study by Meyer et al. that 
included 191 patients with recent oncet RA 
followed for 5 years. Their serum samples 
were examined for ACPA, and erosions 

female 
83% 

male 
17% 

distribution of patients 
according to sex 

sex Ratio(F:M)=4.9:1 

female male 



 
 
 
 

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308 

 

were scored using Sharp scores modified 
as described by van der Heijde. Their 
results suggested that odds of a complete 
Sharp score increase after 5 years was 
significantly higher in patients with ACPA 
[11]. 

 It confirms that patients with erosive 
disease had significantly higher ACPA 
titers than those with non-erosive disease; 
consequently, high titers of ACPA 
antibodies are associated with more 

aggressive disease, as measured by 
significantly higher Sharp scores[6]. 

 Finally, this study showed the effect of 
DMARD naïve period and the disease 
duration on erosion formation, as the 
median of DMARD naïve period                     
and the median disease duration                
were significantly higher in                
patients with erosive disease             
compared to patients with non-erosive 
disease [12]. 

 

Table 1. Characteristics of patients with erosive and non-erosive disease 
 

Characteristics Erosive 
Disease(n=44) 

Non erosive 
disease(n=10) 

Test used P-
value 

The 
statistical 
significance 

Disease duration (yr) 
Median (IQR) 

3.5 (1-20) 2 (1-3) Mann 
Whitney  

0.03 S 

DMARD Naïve period 
(month) 
Median (IQR) 

12 (0-60) 10.5 (0-24) Mann 
Whitney 

0.04 S 

RF positivity (%) 31 (70.45) 6 (60) Chi-square  0.07 N.S 

RF positivity (U/ml) 
Median (IQR) 

47 (1-192) 30 (10-210) Mann 
Whitney 

0.002 S 

Median ACPA titer 
(U/ml) 
Median (IQR) 

16.2 (5.1-300) 7.5 (5.4-38) Mann 
Whitney 

0.001 S 

DMARD: disease modifying anti rheumatic drugs ACPA: anti citrullinated peptides antibody S: Statistically 
significant N.S: Statistically not significant 

 

 
 

Fig. 2. Showing high positive correlation between ACPA titers and SHARP scores. R=0.7, 
p=0.0001 

  

0 

50 

100 

150 

200 

250 

300 

350 

400 

0 50 100 150 200 250 300 350 

SH
A

R
P
 

ACPA  
U/ML 

Sharp 



 
 
 
 

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309 

 

5. CONCLUSION 
 

 ACPA titers are reliable predictors of 
erosive disease, in addition to the fact of 
their ability to predict the cumulative 
structural and radiological damage is 
superior to RF [6,13]. 

 

 ACPA is very important serological marker 
in identifying patients with worse prognosis 
who may develop more severe structural 
damage, and need early aggressive 
treatment and consequently improves their 
clinical outcome and reduce joint damage 
and disability[14]. 

 

 Determination of ACPA are extremely 
valuable marker which is especially useful 
in RF negative patients with early arthritis 
who did not yet fulfill the diagnostic criteria 
of RA [1,14]. 

 

CONSENT AND ETHICAL APPROVAL 
 
This study was reviewed and approved by the 
moral Committee of the Tishreen University 
Hospital. As per international standard or 
university standard guideline participant consent 
has been collected and preserved by the 
authors. 
 

ACKNOWLEDGEMENTS 
 
We wish to thank doctors and technicians in 
laboratory and Radiology departments of 
Tishreen University Hospital who worked with us. 
We would like to thank Miss Elissar Hejazia, Dr. 
Leen Doya, and Dr. Rawa Saad for technical 
help. We would like to thank the assistance 
provided by Prof. Dr. Ahmad Chreitah. 

 
COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 

 
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provided the original work is properly cited. 
 
 

 

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