J Nephropharmacol. 2017; 6(2): 98–105.

NPJ
http://www.jnephropharmacology.com DOI: 10.15171/npj.2017.12

Journal of Nephropharmacology

Evaluation of anti-mutated citrullinated vimentin

antibodies, anti-cyclic citrullinated peptide
antibodies in patients with rheumatoid arthritis
in comparison with other rheumatic diseases; a
nephrology point of view
Alireza Sadeghi1, Aiyoub Pezeshgi1, Arezoo Karimimoghaddam2, Minoosh Moghimi1, Koorosh Kamali 3, Mahsa
Naseri1, Abdolreza Esmaeilzadeh4*
1
Department of Internal Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
2
Department of Ophthalmology, Zanjan University of Medical Sciences, Zanjan, Iran
3
Department of Biostatistics, Zanjan University of Medical Sciences, Zanjan, Iran
4
Department of Immunology & Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran

ARTICLEINFO ABSTRACT

Article Type:
Introduction: Rheumatoid arthritis (RA) is one of the most common autoimmune rheumatic
Original
disease with a chronic and progressive inflammatory disorder manifestations leading
to articular cartilage damage, and disability, and also renal involvement. It seems that
Article History:
recruitment of tests based on high specific and sensitive serological immunobiomarkers
Received: 28 November 2016
removes these mentioned gaps. Additionally, the results of laboratory tests, assist to reach an
Accepted: 2 May 2017
accurate prognosis and real estimation of the patient’s clinical statue especially hospitalized
ePublished: 14 May 2017
individuals in intensive care units.
Objectives: The aim of this study is assessment and titration of some autoantibodies as
Keywords:
anti-mutated citrullinated vimentin (anti-MCV), anti-cyclic citrullinated peptides (anti-
Rheumatoid arthritis

Original
CCP), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in RA patients in
Anti-mutated citrullinated vimentin
comparison to patients with other forms of rheumatologic diseases.
Anti-cyclic citrullinated peptides
Patients and Methods: This descriptive study was conducted from January to June 2012 in
Diagnosis
Zanjan province on 100 patients with RA and 100 patients with other rheumatic disease that
Prognosis
were randomly selected. All necessary data of clinical history for the patients was extracted
Immunobiomarker
from their medical records. After delivering antecubital venous blood (7 mL) to hematology
ward of laboratory, quantative ELISA test was performed for autoantibodies.
Results: Anti-MCV tests showed 72% positivity in RA group compared to 10% positivity in
other group of rheumatic diseases. There was a significant correlation between positivity of
anti-MCV and RA disease. Mean anti-MCV titer is 236.23 ± 2.319 U/mL in RA group and
28.75 ± 0.432 U/mL in other disease group. In this study anti-MCV antibodies had diagnostic
sensitivity of 81.7% (versus anti-CCP), diagnostic specificity of 72.22%, positive and negative
predictive value 93.05% and 46.42%, respectively.
Conclusion: According to results of this study, not only anti-MCV measurement but also
anti-CCP assist to early diagnosis of RA. Results of the recent study could not show definite
correlation between anti-MCV and disease activity. The result of this study may be helpful
for renal involvement in RA patients, whereas evaluation on this aspect of RA patients seems
essential.

Implication for health policy/practice/research/medical education:

According to immunological manifestations of rheumatoid arthritis (RA) and occurrence of renal disorder in some RA patients,
serological immunobiomarkers help to accurate diagnosis and follow up of clinical course of this disease.
Please cite this paper as: Sadeghi A, Pezeshgi A, Karimimoghaddam A, Moghimi M, Kamali K, Naseri M, et al. Evaluation
of anti-mutated citrullinated vimentin antibodies, anti-cyclic citrullinated peptide antibodies in patients with rheumatoid
arthritis in comparison with other rheumatic diseases; a nephrology point of view. J Nephropharmacol. 2017;6(2):98-105. DOI:
10.15171/npj.2017.12.

*Corresponding author: Abdolreza Esmaeilzadeh, Ph.D; Email: [email protected]

 Evaluation of anti-MCV and anti CCP in rheumatoid disease

Introduction duration, prognostic implication for renal involvement in

Rheumatoid arthritis (RA) is one of the most common the course of RA and presence of HLA shared epitopes
autoimmune rheumatic disease of an ambiguous and (27-31).
complicated etiology characterized by a chronic, multi- A functional member of this family is anti-cyclic
systemic and progressive inflammatory disorder affecting citrullinated protein (anti-CCP) antibody, which is now
synovial joints (1,2), leading to functional capacity another most commonly used laboratory test for RA
diminution, articular cartilage damage (3-5), deformity, diagnosis and as most widely used members of ACPA
disability and substantial economic costs (6-9). The global particularly in adults. Cyclic citrullinated protein/
prevalence of RA ranges between 0.5%-1% varies upon peptides (CCP) are purified proteins containing modified
gender, population and ethnicity mostly in developing arginine residues (citrulline), serve as antigen. Anti-CCP
countries in young women and elderly people (3,5,10). is now used as a classification criterion of RA with 96-
Above all, due to the aggressive nature and severity of 99% specificity. This autoantibody, due to the appearance
the clinical manifestations of the disease process, also before clinical symptoms of RA, validates initial immune
inaccuracy in the RA early diagnosis after symptoms onset, dysregulation before disease manifestation. The positive
it is potentially recommended to differentiate between test for anti-CCP may predict the transformation of
persistent RA and other forms of rheumatic diseases; undifferentiated arthritis into RA (6,20,26,32).
while early diagnostics and prognostics approaches leads The probability of developing RA from undifferentiated
to prevent unwanted irreversible joint damages (8,11,12). arthritis in patients with positivity in anti-CCP is 90%,
For long times, diagnosis of RA has been established on whereas 30% in those with negative test (33). In a study, the
radiological manifestations of the diseases. Rheumatoid positive predictive value for RA progression was 80% and
factor (RF) test is applied routinely in laboratories for this was increased when two or three other tests were used
RA diagnosis. RF is an auto-antibody (chiefly low affinity together. Several studies suggest that combination of anti-
IgM type) against the FC portion of IgG immunoglobulin CCP with RF may yield better to reach an efficaciously
molecule that serological basis for this factor is optimum diagnosis. Another advantage of anti-CCP
agglutination method. This factor is not a specific sensitive positivity is in RF seronegative patients in particular at
immunobiomarker and is detectable in other rheumatic early stages of the disease (6,34,35).
diseases, chronic inflammatory conditions, Sjögren’s In recent years, studies have been focused on anti-mutated
syndrome and even healthy elderly people. A substantial citrullinated vimentin (anti-MCV) antibodies because of
correlation has been observed between RF positivity and a higher diagnostic value in comparison with anti-CCP
disease progression. This factor is routinely found in 50%- and RF (26).
80% of RA patients and quantified by sandwich ELISA Anti-MCV is another member of ACPA family, reacting
method (3,7,8,12-14). with vimentin, which acts as carriers for citrulline hapten.
Many efforts have been made for a proper RA diagnosis Citrullination is a post-translational modification of
route. A number of autoantibodies associated to RA have arginine residues which is generalized in the RA patient’s
been clarified. It is demonstrated that autoantibodies such synovium (36-39). There are many studies have compared
as anti-perinuclear factors (APFs), anti-keratin antibodies anti-MCV and anti-CCP for their diagnostic value in RA,
(AKAs), anti-RA33 antibodies, antibodies against several declaring 80% sensitivity. Anti-MCV chiefly associates
specific antigens, including type II collagen, fibrinogen with higher levels of the disease activity score (DAS28)
and α-enolase displayed their challenging insufficiency (40) and joint damages. This accelerates early diagnosis,
in terms of specificity and sensitivity than others (9,15- reliable progression follow up, assessment of functional
18). Although many attempts have been done for RA disability, and response to drug therapy (27,41-45).
diagnosis, new serological markers are still required. In some studies, it is demonstrated that anti-MCV
Circulating non-RF antibodies have been considered to antibodies may be precious factor for RA diagnose in anti-
be of potential diagnostic value with more significant CCP-negative patients. Moreover, anti-MCV antibodies
specificity and sensitivity (6,15-18). could be practical in monitoring the effects of infliximab
Instead, the current laboratory diagnostics of RA therapy and also in RF and anti-CCP negative juvenile
particularly early RA, is based on a highly specific markers idiopathic arthritis patients (46-50), as well as a potential
such as anti-citrullinated proteins/peptides antibodies predictor for RA associated lung diseases or even renal
(ACPA). They have more specificity (94%-99%) and involvement. In addition, due to a lower false positivity
reasonable sensitivity (66%-88%) than RF, in addition of of the anti-CCP in hepatitis C infected patients which
prognostic relevance, high predictive value in progression may present arthralgia or synovitis. Hence, this factor
rate of the disease and disease activity (19-22). These large (anti-MCV) can be recruited for RA diagnosis for these
family glitter as one of the promising diagnostic markers individuals (51-53). Thus, it is suggested that combination
for early onset of RA according to the 2010 ACR/European of anti-MCV, anti-CCP and RF are significant for early
League against Rheumatism criteria for diagnosis and screening of RA (32).
outcome prediction purposes at RA field (23-26). Also,
several members of this autoantibody family have been Objectives
postulated to play a role in RA pathogenesis, disease According to above information, the purpose of this study

http://www.jnephropharmacology.com Journal of Nephropharmacology, Volume 6, Number 2, July 2017 99

 Sadeghi A et al

was to assess the titration of four factors including anti- microtiter wells for 30 minutes at room temperature. Plates
CCP2, erythrocyte sedimentation rate (ESR), C-reactive were washed three times and incubated with peroxidase-
protein (CRP) and anti-MCV in a group of Iranian labeled detecting anti-human IgG-conjugate for 15
patients with RA and other rheumatic diseases. minutes. After washing and substrate addition, microplate
was incubated for 15 minutes. Color development was
Patients and Methods stopped with HCl 1M solution, and the optical density
Patients (OD) was measured. Results were expressed in U/mL
This cross-sectional study was conducted from January using a simple point-to-point curve-fitting method.
to June 2012, at Valiasr Rheumatology Clinic, Zanjan, Values of 20.0 IU/mL or greater were considered to be
Iran. One hundred patients with clinically active RA were abnormal according to manufacturer’s recommendations.
randomly selected and enrolled, who met the ACR 1987 In all 100 RA patients, DAS28 was calculated.
classification criteria. The duration of RA ranged from ESR tests were measured by the Westergren method.
6 months to 6 years for them was registered. All patients Serum CRP concentrations were determined by immune
were treated with prednisolone, hydroxychloroquine nephelometry methods on a Turbox nephelometer (Orion
and methotrexate. None of them, received biologic agent Diagnostica, Finland). The titer of 6 mg/L was considered
therapy. Also 100 subjects were recruited as control positive for CRP.
including patients with other rheumatic diseases (SLE,
Behcet’s disease and seronegative arthritis). Ethical issues
DAS28 ≤2.6 was considered inactive disease, 2.6-3.2 as The research followed the tenets of the Declaration of
mild, 3.2-5.1 moderate and more than 5.1, high for disease Helsinki; informed consent was obtained. This study was
activity. approved by the Ethics Committee of Zanjan University of
Medical Sciences (Ethical code# 12/91-602-01).
Laboratory methods
Participants were recruited to come to the laboratory. Statistical analysis
From the total 200 subjects, 7 mL of peripheral venous Data were analyzed using SPSS version 18 (SPSS Inc, USA).
blood was withdrawn aseptically by an authorized Descriptive results are shown as number, percent, mean
supervisor with sterile gauge needles from each of the two and standard deviation (SD). For comparing the results,
groups and collected in vacutainer blood collection tubes the quantitative variables were analyzed with independent
containing sodium heparin. Around 3 mL of collected t test and qualitative variables with chi-square test.
blood were left to clot for 15 minutes, then centrifuged. Fisher’s exact test was also applied. Sensitivity, specificity,
After centrifugation, sera were put into aliquots and correlation coefficient and measure of agreement (Kappa)
stored at -20°C until assayed for anti-MCV and anti-CCP2 was determined. Statistical significance was considered
antibodies for both patients and controls groups. Anti- when P < 0.05.
CCP2 and anti-MCV tests were performed on all samples
as follow: Results
The anti-CCP2 test was done by using Euroimmun kit Table 1 indicates demographic information of all patients.
(Lübeck, Germany). Anti-CCP2 antibodies were measured Of 100 patients with RA, 73 were females (73%) and 27
by quantitative enzyme-linked immunosorbent assay were males (27%). The control group consisted of 40
(ELISA) kit supplies by INOVA Diagnostics (Cat. NO males (40%) and 60 females (60%). The mean ± SD age
570139, Lebanon) for the measurement of IgG anti-CCP2 of patients was 44.89 ± 1.427 years in RA group (range 18-
antibodies in patients’ sera. The level of greater than 5 RU/ 74 years old) and 34.89 ± 1.219 years in the control group
mL was considered positive. The CCP2 antigen is bound (range 13-70 years old) (Table 1).
to the surface of a microwell plate, allowing any present In the RA group, distribution of positive cases according
CCP2 antigens bind to the immobilized IgG coating to DAS28 was recorded 33 patients (22%) in remission,
antibodies. A second incubation allowed the enzyme 21 (14%) mild disease activity, 69 (46%) moderate activity
labeled detecting antihuman IgG bind to any patient and 27 (18%), high activity.
antigens that have been attached to the microwells and In the RA patients group, anti-MCV was positive in 72
formed a complex. After washing the unbound enzyme cases (72%) of RA and 10 cases (10%) of controls. Chi-
labeled anti-human IgG, the remaining enzyme activity
was measured by adding a chromogenic substrate. Next
to adding stop solution for color development inhibition, Table 1. Demographic information of patients and control group

measuring the intensity of the yellow color was done by a Demographic RA patients
Control group; other
spectrophotometric ELISA reader. A titer above 20 units parameters n = 100
rheumatic disease P value
n = 100
was considered as positive.
The anti-MCV antibodies test was done, using Orgentec Age (y) 44.89 ± 1.427 34.89 ± 1.219 0.264
Diagnostika kit (GmbH, Mainz, Hamburg Germany) Gender 0.221
according to the manufacturer’s instructions. Serum Female 73 60
Male 27 40
samples were diluted 1:100 and incubated on MCV coated

100  Journal of Nephropharmacology, Volume 6, Number 2, July 2017 http://www.jnephropharmacology.com

 Evaluation of anti-MCV and anti CCP in rheumatoid disease

square test revealed a statistically significant relationship Table 2. Distribution of anti-MCV tests results in RA patients and in
patients with other rheumatologic diseases
between anti-MCV positivity and RA diagnosis. Notably,
more frequency of anti-MCV positivity was observed in Study groups
P value
RA group than to other (Table 2). Anti-MCV RA patients Patients suffering other
The results also showed that the anti-MCV titer mean in (n = 100) rheumatic disease (n = 100)
Positive 72 (72%) 10 (10%) 0.001
the RA group is statistically higher than other rheumatic
diseases (236.23 ± 2.32 U/mL and 28.75 ± 0.432 U/mL
 
Negative 28 (28%) 90 (90%) 0.001
respectively; P < 0.001).
Table 3 represents the frequency distribution of anti- Table 3. Anti-MCV positivity in other rheumatologic diseases
MCV positivity in other rheumatic disease. There was subgroups
no significant statistical difference between anti-MCV Anti-MCV Seronegative arthritis SLE Behcet’s diseases
positivity and each of three other rheumatic diseases. Positive 4 (40%) 6 (60%) 0 (0%)
Table 4 shows anti-CCP and anti-MCV positivity for RA
Negative 54 (60%) 29 (32.2%) 7 (7.8%)
group. 67% of cases were simultaneously anti-CCP and
anti-MCV positive and 13% anti-CCP and anti-MCV
negative. Table 4 displays sensitivity and specificity of anti- Table 4. Anti-MCV in comparison with anti-CCP tests results in RA
MCV in comparison with anti-CCP tests (sensitivity = patients
0.82 and specificity = 0.72). In RA patients group, both Anti-MCV
Anti-CCP P value
anti-CCP and anti-MCV were negative in 13 cases, while Positive Negative
positive anti-CCP and negative anti-MCV were detected Positive 67 (67%) 5 (5%)
0.001
in 15 cases and negative ACCP and positive anti-MCV Negative 15 (15%) 13 (13%)
seen in 5 cases. The kappa measure of agreement was
0.810 for these results. The kappa coefficient for ACCP
and anti-MCV was calculated at 0.443 (0.21-0.61). Anti-CCP Titer
Figure 1 shows statistically significant correlation between 1200

anti-CCP and anti-MCV titer in RA patients (P = 0.001).

1000
Figures 2 and 3 show reverse correlation between anti-
MCV and CRP/ESR titers in RA patients. 800
Table 5 shows correlation between anti-MCV titer and CRP R² = 0.0963
and ESR in RA and control group which is not statistically 600
CCP

significant according to coefficient correlation.

Table 6 shows relation between anti-MCV titer, CRP and 400
ESR in both study groups.
200
Discussion Anti-MCV Titer
0
In this study, we compared the diagnostic values of
0 500 1000 1500 2000 2500 3000
anti-CCP and anti-MCV. The aim of this study was to
distinguish more informative test for diagnosing RA.
Figure 1. Correlation between anti-CCP and anti-MCV titer in
Previous studies yielded controversial results without RA patients.
a definite agreement to conclude a more accurate test.
There is also no comprehensive study in an Iranian cohort
of RA patients. aggregation and activation of complement system
On the other hand, it is obvious that, totally, mentioned components, release of some enzymes and kinin. The
immunoserological factors (anti-MCV and anti-CCP), prevalence of these kidney disorders ranges from 5% to
are the result of an immune response to an identified 50% in RA patients. In addition, variation in the antigen
antigen. In addition to RA, increased concentrations of size, immunoglobulin classes and antigen antibody ratio
circulating soluble immune complexes are highlighted are significant determinants in localization or expansion
in several pathological situations such as systemic lupus of the disease (54,55).
erythematous, chronic inflammatory bowel diseases Hence, with a nephrologic point of view, we decided to
(IBD), various forms of glomerulonephritis and even generalize our results for medicine specialists to reach
disseminated malignancies (54). an accurate prognosis and real estimation of the patient’s
Glomerulonephritis and renal co-morbidities are one clinical statue especially at intensive care units.
of the frequent, but not well recognized and diagnosed, In a study by Hurkmans et al, for progression prediction
manifestations of the RA. It is demonstrated that of the disease from undifferentiated arthritis to RA, the
repeatedly administration of antigen leads to chronic anti-CCP test had presented very good specificity and
nephritis, as an important causes of death subsequent PPV. Anti-MCV did not seem to be more informative,
to chronic infections. Additionally, other complications and adding RF and anti-MCV tests to anti-CCP2 did not
such as vasculitis due to immune complexes deposition, enhance the diagnostic value of the laboratory test and it is

http://www.jnephropharmacology.com Journal of Nephropharmacology, Volume 6, Number 2, July 2017 101

 Sadeghi A et al

CPR
CRP Titer
Titer
to be 79.6% and specificity 96.6%. They detected that test
90
positivity was accompanied with a higher DAS28 (56). In
80
addition, this finding has been confirmed by Syversen et
70 al, who reported more advanced joint damage in patients
60 with anti-MCV positivity (57).
CRP
50 In most of researches, the sensitivity of anti-MCV was
40 somehow higher than anti-CCP, but anti-CCP was more
30 specific (34,56,58,59). The similar results have been
20 demonstrated in another studies while investigators found
10 R² = 0.0236 that in RF negative patients, the sensitivity of anti-MCV is
Anti-MCV Titer high (43.8% versus 30%) (56).
0
0 500 1000 1500 2000 2500 3000 Our study did not show obvious differences between
sensitivity and specificity of anti-CCP and anti-
Figure 2. Correlation between anti-MCV and CRP titers in RA MCV (sensitivity 85%, 81%, specificity 96% and
patients 95%, respectively). The analysis of the above results
displayed kappa of high agreement between these two
tests (kappa = 0.81), and correlation coefficient of 0.63
ESR Titer
140 (P = 0.001) which means that both tests have similar value.
120
In other words, anti-CCP and anti-MCV positivity usually
coincide.
100
In the study of Arnett et al, a significant correlation
ESR
80 between anti-MCV and ACCP was seen (60). However,
60
in our study, in a small proportion of our cases, this result
was not accurate, while 10 cases (6.7%) had positive
40
anti-CCP and negative anti-MCV, and four cases (2.7%)
R² = 0.0311
20 had negative anti-CCP and positive anti-MCV. It was
Anti-MCV Titer
0
slightly different in the study of Majithia et al in which
0 500 1000 1500 2000 2500 3000 the proportion of positive anti-MCV in ACCP cases was
equal to the proportion of positive ACCP in anti-MCV
Figure 3. Correlation between anti-MCV and ESR titer in RA
negative patients (61).
patients.
In ROC analysis, the level for each test with 100%
specificity was determined. This was 9.8 U/mL for anti-
Table 5. Relationship between anti-MCV titer and CRP and ESR in CCP (2 times of the laboratory cut-off point) and 89.5 U/
study groups
mL for anti-MCV (4 times of the laboratory cut-off point).
Anti-MCV titer The sensitivity of the tests was 81% and 57%, respectively.
Variables Other rheumatic RA patients, P value The latter means that anti-CCP with the level of 2 times
disease, n = 100 n = 100
more than normal and 81% sensitivity is specific for
ESR (mg/L) 39.5±2.15 43.95±8.98 < 0.001
diagnosis of RA. However, for anti-MCV, this level is four
CRP (mm/h) 17.28±1.48 19.22±1.71 < 0.001
times more than normal with a sensitivity of 57%. Below
these levels, anti-MCV has less specificity. This might be
Table 6. Pearson’s correlation test between anti-MCV titer and CRP a reason that anti-MCV has been introduced as a new
and ESR in study groups biomarker for diagnosis of ankylosing spondylitis (62).
Pearson’s correlation P value Positive anti-MCV was also reported in SLE, Sjögren’s
Variables Other rheumatic Other rheumatic syndrome, psoriatic arthritis, Epstein-Barr virus and
RA RA
disease disease hepatitis C virus infected patients (56,59). Because of low
ESR (mm/h) 0.09 0.12 0.220 0.356 proportion of non-RA controls in our study, we obtained
CRP (mg/L) 0.12 0.12 0.226 0.127
these results.

concluded that a single test was efficient (54). Conclusion

High specificity, more than 90% PPV for ACCP and a poor As a whole, we came to this conclusion that the titer of anti-
outcome for ACCP positive RA patients were reported in MCV in RA patients are significantly higher, comparing
a review published in 2009 (55). In a recent meta-analysis, to the other autoimmune diseases as systemic lupus
16 studies on anti-MCV were analyzed. Sensitivity, erythematous, Behcet’s disease, seronegative arthritis.
specificity, positive likelihood rate (LR), negative LR and Furthermore, the high sensitivity of anti-MCV in RA
diagnostic odds ratios (ORs) were estimated to be 0.77, diagnosis, beside of anti-CCP which has a great specificity
0.89, 7.24, 0.28 and 29.66 respectively (14). in diagnosis of RA, can be helpful in differentiation of RA
In another study, sensitivity of anti-MCV was reported from other types of arthritis.

102  Journal of Nephropharmacology, Volume 6, Number 2, July 2017 http://www.jnephropharmacology.com

 Evaluation of anti-MCV and anti CCP in rheumatoid disease

Limitations of the study doi: 10.1111/j.1756-185X.2010.01552.x.

This is a single center study with a limited proportion of 9. Dejaco C, Klotz W, Larcher H, Duftner C, Schirmer M,
patients. We strongly suggest larger studies on this aspect Herold M. Diagnostic value of antibodies against a modified
of RA. citrullinated vimentin in rheumatoid arthritis. Arthritis Res
Ther. 2006;8R119. doi: 10.1186/ar2008.
10. Renger F, Bang H, Feist E, Fredenhagen G, Natusch A,
Authors’ contribution
Backhaus M, et al. Immediate determination of ACPA and
AS, AP, and MM acted as rheumatologist specialist rheumatoid factor-a novel point of care test for detection of
advisor, nephrologist specialist advisor, and oncologist anti-MCV antibodies and rheumatoid factor using a lateral-
advisor, respectively. In addition, AS did literature flow immunoassay. Arthritis Res Ther. 2010;12:R120. doi:
review and clinical improvement. KK performed 10.1186/ar3057.
statistical analyses. ARE contributed as corresponding 11. Greiner A, Plischke H, Kellner H, Gruber R. Association
author to conceptualization, study design and project of anti‐cyclic citrullinated peptide antibodies, anti‐citrullin
administration, data interpretation helps, revision, edition antibodies, and IgM and IgA rheumatoid factors with
and approvement of final version of manuscript. MN serological parameters of disease activity in rheumatoid
organized data collecting, literature review, and scientific arthritis. Ann N Y Acad Sci. 2005;1050:295-303. doi:
10.1196/annals.1313.031.
writing.
12. Aggarwal R, Liao K, Nair R, Ringold S, Costenbander KH.
Anti–citrullinated peptide antibody assays and their role in
Conflicts of interest the diagnosis of rheumatoid arthritis. Arthritis Care Res.
The authors declare no conflict of interest. 2009;61:1472-83. doi: 10.1002/art.24827.
13. Trouw LA, Mahler M. Closing the serological gap:
Funding/ Support promising novel biomarkers for the early diagnosis of
This project is financially supported by a grant from rheumatoid arthritis. Autoimmun Rev. 2012;12:318-22. doi:
Zanjan University of Medical Sciences (Grant# 12/91- 10.1016/j.autrev.2012.05.007.
602-01) and was extracted from Mahsa Naseri residential 14. Bartoloni E, Alunno A, Bistoni O, Bizzaro N, Migliorini
thesis (Thesis #12/91-602-01). P, Morozzi G, et al. Diagnostic value of anti-mutated
citrullinated vimentin in comparison to anti-cyclic
citrullinated peptide and anti-viral citrullinated peptide 2
References
antibodies in rheumatoid arthritis: an Italian multicentric
1. Ağıllı M, Ekinci Ş, Aydın FN, Şener İ, Parlak A, Yaman H.
study and review of the literature. Autoimmun Rev.
Anti-cyclic citrullinated peptide antibody (anti-CCP) and
2012;11:815-20. doi: 10.1016/j.autrev.2012.02.015.
diagnostic value for rheumatoid arthritis. TAF Prev Med
15. Marcelletti JF, Nakamura RM. Assessment of serological
Bull. 2014;13:83-8. doi: 10.5455/pmb.1-1361823179.
markers associated with rheumatoid arthritis: diagnostic
2. Kurti M, Ylli Z, Petrela E, Sulcebe G. Diagnostic value of
autoantibodies and conventional disease activity markers.
specific auto-antibody markers in albanian patients with
Clin Appl Immunol Rev. 2003;4:109-23. doi: 10.1016/
rheumatoid arthritis. Int J Health Sci Res. 2014;4(10):27-33.
S1529-1049(03)00048-5.
3. Lutteri L, Malaise M, Chapelle J-P. Comparison of second-
16. Sizova L. Diagnostic value of antibodies to modified
and third-generation anti-cyclic citrullinated peptide
citrullinated vimentin in early rheumatoid arthritis.
antibodies assays for detecting rheumatoid arthritis. Clin
Hum Immunol. 2012;73:389-92. doi: 10.1016/j.
Chim Acta. 2007;386:76-81. doi: 10.1016/j.cca.2007.08.002
humimm.2012.01.007.
4. Tian F, Li J, Tuo H, Ling Q, Zeng S, Wen Z, et al. The anti-
17. Snir O, Widhe M, Hermansson M, von Spee C, Lindberg J,
mutated citrullinated vimentin antibody as a potential
Hensen S, et al. Antibodies to several citrullinated antigens
predictor for rheumatoid arthritis associated interstitial
are enriched in the joints of rheumatoid arthritis patients.
lung diseases. Int J Clin Exp Med. 2016;9:6813-8.
Arthritis Rheum. 2010;62:44-52. doi: 10.1002/art.25036.
5. Zahran WE, Mahmoud MI, Shalaby KA, Abbas MH. Unique
18. Zhu T, Feng L. Comparison of anti‐mutated citrullinated
correlation between mutated citrullinated vimentine IgG
vimentin, anti‐cyclic citrullinated peptides, anti‐glucose‐6‐
autoantibodies and markers of systemic inflammation
phosphate isomerase and anti‐keratin antibodies and
in rheumatoid arthritis patients. Indian J Clin Biochem.
rheumatoid factor in the diagnosis of rheumatoid arthritis
2013;28:272-6. doi: 10.1007/s12291-012-0272-1.
in Chinese patients. Int J Rheum Dis. 2013;16:157-61. doi:
6. Vallbracht I, Helmke K. Additional diagnostic and clinical
10.1111/1756-185X.12040.
value of anti-cyclic citrullinated peptide antibodies
19. Fabris M, De Vita S, Blasone N, Visentini D, Pezzarini E,
compared with rheumatoid factor isotypes in rheumatoid
Pontarini E, et al. Serum levels of anti-CCP antibodies, anti-
arthritis. Autoimmun Rev. 2005;4:389-94. doi: 10.1016/j.
MCV antibodies and RF IgA in the follow-up of patients
autrev.2005.02.001.
with rheumatoid arthritis treated with rituximab. Auto
7. Tampoia M, Brescia V, Fontana A, Maggiolini P, Lapadula G,
Immun Highlights. 2010;1:87-94. doi: 10.1007/s13317-010-
Pansini N. Anti-cyclic citrullinated peptide autoantibodies
0013-5.
measured by an automated enzyme immunoassay:
20. Gyulai R. Higher levels of autoantibodies targeting mutated
analytical performance and clinical correlations. Clin Chim
citrullinated vimentin in patients with psoriatic arthritis
Acta. 2005;355:137-44. doi: 10.1016/j.cccn.2004.12.017.
than in patients with psoriasis vulgaris. Clin Dev Immunol.
8. Maraina CHC, Nurdayana AK, Rusni D, Azwany Y.
2013;2013:474028. doi: 10.1155/2013/474028.
Diagnostic value of anti‐modified citrullinated vimentin
21. Meyer O. Anti-citrullinated peptide/protein antibodies
in rheumatoid arthritis. Int J Rheum Dis. 2010;13(4):335-9.
and structural prognosis of rheumatoid arthritis: quantity

http://www.jnephropharmacology.com Journal of Nephropharmacology, Volume 6, Number 2, July 2017 103

 Sadeghi A et al

versus quality. J Rheumatol. 2012;39:675-6. doi: 10.3899/ arthritis. Am Fam physician. 2011;84:1245-52.
jrheum.120009. 34. Alamanos Y, Voulgari PV, Drosos AA. Incidence
22. Shiozawa K, Kawasaki Y, Yamane T, Yoshihara R, Tanaka Y, and prevalence of rheumatoid arthritis, based on the
Uto K, et al. Anticitrullinated protein antibody, but not its 1987 American College of Rheumatology criteria: a
titer, is a predictor of radiographic progression and disease systematic review. Semin Arthritis Rheum. 2006;36:182-8.
activity in rheumatoid arthritis. J Rheumatol. 2012;39:694- doi:10.1016/j.semarthrit.2006.08.006.
700. doi: 10.3899/jrheum.111152. 35. Bizzaro N, Bartoloni E, Morozzi G, Manganelli S, Riccieri V,
23. Degboé Y, Constantin A, Nigon D, Tobon G, Cornillet M, Sabatini P, et al. Anti-cyclic citrullinated peptide antibody
Schaeverbeke T, et al. Predictive value of autoantibodies titer predicts time to rheumatoid arthritis onset in patients
from anti-CCP2, anti-MCV and anti-human citrullinated with undifferentiated arthritis: results from a 2-year
fibrinogen tests, in early rheumatoid arthritis patients with prospective study. Arthritis Res Ther. 2013;15:R16. doi:
rapid radiographic progression at 1 year: results from the 10.1186/ar4148.
ESPOIR cohort. RMD Open. 2015;1:e000180. doi:10.1136/ 36. El Shazly RI, Hussein SA, Raslan HZ, Elgogary AA. Anti-
rmdopen-2015-000180. mutated citrullinated vimentin antibodies in rheumatoid
24. Lakos G, Soós L, Fekete A, Szabó Z, Zeher M, Horváth I, arthritis patients: Relation to disease activity and
et al. Anti-cyclic citrullinated peptide antibody isotypes manifestations. The Egyptian Rheumatologist. 2014;36:65-
in rheumatoid arthritis: association with disease duration, 70. doi: 10.1016/j.ejr.2013.12.009.
rheumatoid factor production and the presence of shared 37. El-Fetou S, Abozaid HS. Diagnostic value of antibodies
epitope. Clin Exp Rheumatol. 2008;26:253. against a modified citrullinated vimentin in rheumatoid
25. Mathsson L, Mullazehi M, Wick MC, Sjöberg O, van arthritis. Open J Rheumatol Autoimmune Dis. 2013;3:185-
Vollenhoven R, Klareskog L, et al. Antibodies against 91. doi: 10.4236/ojra.2013.34029
citrullinated vimentin in rheumatoid arthritis: higher 38. Juarez M, Bang H, Hammar F, Reimer U, Dyke B,
sensitivity and extended prognostic value concerning future Sahbudin I, et al. Identification of novel antiacetylated
radiographic progression as compared with antibodies vimentin antibodies in patients with early inflammatory
against cyclic citrullinated peptides. Arthritis Rheum. arthritis. Ann Rheum Dis. 2016;75:1099-107. doi: 10.1136/
2008;58:36-45. doi: 10.1002/art.23188. annrheumdis-2014-206785.
26. Wagner E, Skoumal M, Bayer P, Klaushofer K. Antibody 39. Nijenhuis S, Zendman AJ, Vossenaar ER, Pruijn GJ.
against mutated citrullinated vimentin: a new sensitive Autoantibodies to citrullinated proteins in rheumatoid
marker in the diagnosis of rheumatoid arthritis. Rheumatol arthritis: clinical performance and biochemical aspects of
Int. 2009;29(11):1315-21. doi: 10.1007/s00296-009-0854-2. an RA-specific marker. Clin Chim Acta. 2004;350:17-34.
27. Szodoray P, Szabó Z, Kapitány A, Gyetvai Á, Lakos G, Szántó doi: 10.1016/j.cccn.2004.07.016.
S, et al. Anti-citrullinated protein/peptide autoantibodies 40. Poulsom H, Charles PJ. Antibodies to citrullinated vimentin
in association with genetic and environmental factors are a specific and sensitive marker for the diagnosis of
as indicators of disease outcome in rheumatoid rheumatoid arthritis. Clin Rev Allergy Immunol. 2008;34:4-
arthritis. Autoimmun Rev. 2010;9:140-3. doi: 10.1016/j. 10. doi: 10.1007/s12016-007-8016-3.
autrev.2009.04.006. 41. Osman AS, Desouky SM, Fattah MDA, Baraka EA,
28. Taylor P, Gartemann J, Hsieh J, Creeden J. A systematic Ramadan AE. Diagnostic value of anti-mutated citrullinated
review of serum biomarkers anti-cyclic citrullinated vimentin versus anti-keratin anti-bodies in early diagnosis
peptide and rheumatoid factor as tests for rheumatoid of rheumatoid arthritis. The Egyptian Journal of Medical
arthritis. Autoimmune Dis. 2011;2011:815038. doi: Microbiology. 2016;25(2):43-48.
10.4061/2011/815038 42. Pruijn GJ, Wiik A, van Venrooij WJ. The use of citrullinated
29. Van Steendam K, Tilleman K, Deforce D. The relevance peptides and proteins for the diagnosis of rheumatoid
of citrullinated vimentin in the production of antibodies arthritis. Arthritis Res Ther. 2010;12:203. doi: 10.1186/
against citrullinated proteins and the pathogenesis of ar2903
rheumatoid arthritis. Rheumatology. 2011;50:830-7. doi: 43. Puszczewicz M, Iwaszkiewicz C. Role of anti-citrullinated
10.1093/rheumatology/keq419 protein antibodies in diagnosis and prognosis of
30. Rodríguez‐Mahou M, López‐Longo FJ, Sánchez‐Ramón S, rheumatoid arthritis. Arch Med Sci. 2011;7:189-94. doi:
Estecha A, García‐Segovia A, Rodríguez‐Molina JJ, et al. 10.5114/aoms.2011.22067.
Association of anti–cyclic citrullinated peptide and anti‐ 44. Vossenaar ER, Deprés N, Lora M, van der Heijden A,
Sa/citrullinated vimentin autoantibodies in rheumatoid Lapointe E, Zendman A, et al. The rheumatoid arthritis
arthritis. Arthritis Care Res. 2006;55:657-61. doi: 10.1002/ specific Sa antigen is citrullinated vimentin. Arthritis Res
art.22089. Ther. 2004;6:R142-50. doi: 10.1186/ar1149
31. García-Berrocal B, González C, Pérez M, Navajo JA, 45. Yousefghahari B, Alhooei S, Soleimani-amiri MJ, Guran A.
Moreta I, Dávila C, et al. Anti-cyclic citrullinated peptide Comparison of sensitivity and specificity of anti-CCP and
autoantibodies in IgM rheumatoid factor-positive anti-MCV antibodies in an Iranian cohort of patients with
patients. Clin Chim Acta. 2005;354:123-30. doi: 10.1016/j. rheumatoid arthritis. Caspian J Intern Med. 2013;4:702-6.
cccn.2004.11.025. 46. Lipinska J, Lipinska S, Kasielski M, Smolewska E. Anti-
32. Infantino M, Manfredi M, Meacci F, Sarzi-Puttini P, Ricci MCV and anti-CCP antibodies—diagnostic and prognostic
C, Atzeni F, et al. Anti-citrullinated peptide antibodies and value in children with juvenile idiopathic arthritis (JIA).
rheumatoid factor isotypes in the diagnosis of rheumatoid Clin Rheumatol. 2016;35:2699-06. doi: 10.1007/s10067-
arthritis: an assessment of combined tests. Clin Chim Acta. 016-3355-1.
2014;436:237-42. doi: 10.1016/j.cca.2014.05.019. 47. Lipinska J, Smolewska E, Brozik H, Stanczyk J. 848 Anti-
33. Wasserman AM. Diagnosis and management of rheumatoid MCV and Anti-CCP antibodies-diagnostic and prognostic

104  Journal of Nephropharmacology, Volume 6, Number 2, July 2017 http://www.jnephropharmacology.com

 Evaluation of anti-MCV and anti CCP in rheumatoid disease

value in children with juvenile idiopathic arthritis. Pediatr 2009:CD006853. doi: 10.1002/14651858.CD006853.pub2.
Res. 2010;68:425. doi: 10.1203/00006450-201011001-00848 55. Deighton C, O’Mahony R, Tosh J, Turner C, Rudolf M,
48. Pang S, Liu H, Huang Y, Liu Y, Dai Y, Zeng P, et al. Group GD. Management of rheumatoid arthritis: summary
Diagnostic performance of anti-citrullinated protein/ of NICE guidance. BMJ. 2009;338:b702. doi: 10.1136/bmj.
peptide antibodies in juvenile idiopathic arthritis. Genet b702.
Mol Res. 2016;15. doi: 10.4238/gmr.15028641. 56. Bang H, Egerer K, Gauliard A, Lüthke K, Rudolph PE,
49. Roland PN, Mignot SG, Bruns A, Hurtado M, Palazzo Fredenhagen G, et al. Mutation and citrullination modifies
E, Hayem G, et al. Antibodies to mutated citrullinated vimentin to a novel autoantigen for rheumatoid arthritis.
vimentin for diagnosing rheumatoid arthritis in anti-CCP- Arthritis Rheum. 2007;56:2503-11. doi: 10.1002/art.22817.
negative patients and for monitoring infliximab therapy. 57. Syversen S, Gaarder P, Goll G, Ødegård S, Haavardsholm
Arthritis Res Ther. 2008;10:R142. doi: 10.1186/ar2570 E, Mowinckel P, et al. High anti-cyclic citrullinated
50. Spârchez M, Miu N, Bolba C, Iancu M, Spârchez Z, Rednic peptide levels and an algorithm of four variables predict
S. Evaluation of anti-cyclic citrullinated peptide antibodies radiographic progression in patients with rheumatoid
may be beneficial in RF-negative juvenile idiopathic arthritis: results from a 10-year longitudinal study. Ann
arthritis patients. Clin Rheumatol. 2016;35:601-7. doi: Rheum Dis. 2008;67:212-7. doi: 10.1136/ard.2006.068247
10.1007/s10067-015-2971-5. 58. Bizzaro N, Mazzanti G, Tonutti E, Villalta D, Tozzoli R.
51. Osman KS, Aly LH, Saedii AA, Abbas HT, Sadek HA. Anti- Diagnostic accuracy of the anti-citrulline antibody assay for
mutated citrullinated vimentin (anti-MCV) antibodies rheumatoid arthritis. Clin Chem. 2001;47:1089-93.
as a diagnostic aid for rheumatoid arthritis. J Clin Cell 59. Richards BL, Whittle SL, Buchbinder R. Muscle
Immunol. 2014;5:263. doi: 10.4172/2155-9899.1000263. relaxants for pain management in rheumatoid arthritis.
52. Vander Cruyssen B, Peene I, Cantaert T, Hoffman I, De Cochrane Database Syst Rev. 2012;1:CD008922. doi:
Rycke L, Veys E, et al. Anti-citrullinated protein/peptide 10.1002/14651858.CD008922.pub2.
antibodies (ACPA) in rheumatoid arthritis: specificity 60. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
and relation with rheumatoid factor. Autoimmun Rev. Cooper NS, et al. The American Rheumatism Association
2005;4:468-74. doi: 10.1016/j.autrev.2005.04.018. 1987 revised criteria for the classification of rheumatoid
53. Kuna AT. Mutated citrullinated vimentin antibodies in arthritis. Arthritis Rheum. 1988;31:315-24.
rheumatoid arthritis. Clin Chim Acta. 2012;413:66-73. doi: 61. Majithia V, Geraci SA. Rheumatoid arthritis: diagnosis and
10.1016/j.cca.2011.10.020. management. Am J Med. 2007;120:936-9. doi: 10.1016/j.
54. Hurkmans E, van der Giesen FJ, Vliet Vlieland TP, Schoones amjmed.2007.04.005
J, Van den Ende EC. Dynamic exercise programs (aerobic 62. Firestein GS. Immunologic mechanisms in the pathogenesis
capacity and/or muscle strength training) in patients of rheumatoid arthritis. J Clin Rheumatol. 2005;11:S39-44.
with rheumatoid arthritis. Cochrane Database Syst Rev.

Copyright © 2017 The Author(s); Published by Society of Diabetic Nephropathy Prevention. This is an open-access article distributed
under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

http://www.jnephropharmacology.com Journal of Nephropharmacology, Volume 6, Number 2, July 2017 105