Role of anti-mutated citrullinated vimentin antibodies in chronic hepatitis C patients and its relation to... The aim of the work was to determine the frequency of anti-MCV antibodies in
Trang 1Original Article
Role of anti-mutated citrullinated vimentin antibodies in chronic
hepatitis C patients and its relation to HCV associated arthritis
a Departments of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
b
Department of Internal Medicine and Rheumatology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
a r t i c l e i n f o
Article history:
Received 29 October 2016
Accepted 5 November 2016
Available online xxxx
Keywords:
Anti-mutated citrullinated vimentin
antibody (anti-MCV)
HCV infection
Arthritis
a b s t r a c t
Aim of the work: To determine the frequency of anti-mutated citrullinated vimentin (anti-MCV) antibod-ies in chronic hepatitis C virus (HCV) patients and its relation to HCV associated arthritis
Patients and methods: The study included 60 HCV patients and 30 age and sex matched control Patients were subgrouped according to the presence and absence of associated arthritis Laboratory investigations were performed and anti-MCV antibodies were measured
Results: The age of the patients ranged between 29 and 75 years (mean 57.65 ± 8.49 years) and they were
38 males (63.3%) and 22 females (36.7%) M:F 1.7:1 32 (53.3%) patients had arthritis while the remaining
28 (46.7%) did not There was a significantly higher anti-MCV antibody level in the patients (median
250 ug/L; range 175–375 ug/L) compared to the control (p < 0.001) There was no significant difference
in the anti-MCV antibodies between HCV patients with and without arthritis (p = 0.15) The HCV patients without arthritis had a significantly higher level of anti-MCV antibody (median 200 ug/L, range 175–
375 ug/L) than the control (median 30 ug/L, range 5–15 ug/L) (p < 0.001) and the area under the curve (AUC) was 0.85 (95% CI 0.69–1, p = 0.004) When the cut-off value for anti-MCV antibody was set at 57.5 ug/L, clinical sensitivity was 80% and specificity was 80% between those without arthritis and the control There was no significant correlation between anti-MCV antibody with various studied parame-ters in the HCV patients
Conclusion: Anti-MCV antibody is significantly increased in HCV patient and has no role in diagnosing HCV-associated arthritis
Ó 2016 Egyptian Society of Rheumatic Diseases Publishing services provided by Elsevier B.V This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
1 Introduction
HCV is a member of the Hepacivirus genus (Flaviviridae family)
that causes hepatitis The World Health Organization (WHO)
esti-mates that about 3% of the world’s population has been infected
with HCV It is well established that HCV is of global importance
affecting all countries, leading to a major global health problem
that requires widespread active interventions for its prevention
and control Chronic hepatitis C was linked to the development
of cirrhosis and hepatocellular carcinoma [1] HCV genotype 4
(HCV-g4) is the most frequent cause of chronic hepatitis C in the
Middle East, North Africa and sub-Saharan Africa Egypt is the
country with the highest worldwide incidence and prevalence of
HCV-4 infections [2] Estimates of HCV antibody prevalence in Egypt is 14.7% with 8–10 million having anti-HCV antibodies and 5–7 million having active infections (i.e., HCV-RNA positive) [3] Extrahepatic manifestations (EHM) are an integral part of the nat-ural history of HCV infection During the disease course, 40–74% of patients infected with HCV might develop at least one EHM[4]and Lapin´ski et al.[5] reported that Rheumatologic complications of HCV infection are variable and include mixed cryoglobulinemia, vasculitis, sicca symptoms, myalgia, arthritis and fibromyalgia Arthralgia is one of the most common EHM in patients with HCV infection or HCV-related cryoglobulinemia[6] The clinical picture
of HCV-related arthropathy varies widely, ranging from pol-yarthralgia to monoarticular or oligoarticular arthritis and sym-metric chronic polyarthritis In particular, monoarticular or oligoarticular involvement affects larger joints and is typically associated with mixed cryoglobulinemia, whereas symmetric pol-yarthritis associated with HCV infection frequently shows a RA-like clinical picture However, compared with RA, HCV-associated
http://dx.doi.org/10.1016/j.ejr.2016.11.002
1110-1164/Ó 2016 Egyptian Society of Rheumatic Diseases Publishing services provided by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).
Peer review under responsibility of Egyptian Society of Rheumatic Diseases.
⇑ Corresponding author at: Department of Internal Medicine and Rheumatology,
Faculty of Medicine, Ain Shams University, Abbasia, Cairo, Egypt Tel.: 002
01227441074.
E-mail address: nowara2005@yahoo.com (N.O El-Azizi).
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j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / e j r
Please cite this article in press as: El Fedawy S et al Role of anti-mutated citrullinated vimentin antibodies in chronic hepatitis C patients and its relation to
Trang 2arthritis is usually less severe and does not cause joint deformities
or rheumatoid nodules[7–9]
Anticitrullinated peptide antibodies (ACPA) are a group of
anti-bodies aganist citrullinated protein/peptide antigens This family of
autoantibodies is an overlapping group of antibodies dependent on
the citrullination of arginine residue of the protein It includes
antiperinuclear factor (APF), antikeratin antibody (AKA),
antifilag-grin antibodies (AFA), anti-Sa (vimentin), and anti-cyclic
citrulli-nated peptide (CCP) antibodies [10] anti-mutated citrullinated
vimentin (anti-MCV) antibodies, member of ACPA family, result
from antibody production against antigens produced from the
citrullination of vimentin[11]
The aim of the work was to determine the frequency of
anti-MCV antibodies in chronic hepatitis C virus patients and its
rela-tion to HCV associated arthritis
2 Patients and methods
The study included 60 HCV patients consecutively collected
from Ain-Shams University Hospitals diagnosed by HCV antibody
and HCV-RNA reverse transcriptase polymerase chain reaction
(RT-PCR) 30 age and sex matched healthy subjects with negative
HCV antibodies were considered as a control group Patients were
subjected to full history taking and complete clinical examination;
with emphasis on articular involvement Patients with any
associ-ated rheumatic disease were excluded from the study The study
was approved by the ethics committee of Ain-Shams University
Hospitals and informed consents from patients or their relatives
were provided The patient group is further subgrouped according
to the presence of arthritis into HCV patients with and without
arthritis
The following laboratory investigations were measured for the
patients: complete blood count (CBC) performed on 5 part
differen-tial automated cell counter coulterÒLH 750 cell counter (Coulter
Corporation, Florida, USA), serum C-reactive protein (CRP) level
using dimensionÒclinical chemistry system (Siemens health care
diagnostic products GmbH, Malburg, Germany) based on particle
enhanced turbidimetric immunoassay technique (cut off value
3.0 mg/L), erythrocyte sedimentation rate (ESR), liver enzymes:
aspartate transaminase (AST) and alanine transaminase (ALT) and
serum albumin using Synchron CX-9 autoanalyzer, Beckman
Instruments., Inc., Fullerton, California USA Serum rheumatoid
fac-tor (RF) was quantitatively determined by Roche/Hitachi cobas
c311 analyzer based on latex bound immunoturbidimetric assay
A positive result was defined as a level of >14.0 U/mL Quantitative
HCV-RNA was done using HCV-RNA reverse transcriptase
poly-merase chain reaction (RT-PCR) within the NS 5’NC gene (Amplicor
HCV, Roche Diagnostics, USA)
Serum mutated citrullinated vimentin (MCV)
anti-body was measured by quantitative sandwich ELISA kit for
detec-tion of anti-MCV (Orgentec Diagnostika GmbH, Mainz, Germany)
It was used according to manufacturer’s instructions with the
rec-ommended cut-off value of 40.0 ug/L
2.1 Statistical analysis
The collected data were analyzed using SPSS (version 20)
statis-tical software package under Windows 7 operating system for IBM
compatible PC The statistical tests used were presented as range
and median for non-parametric data and mean ± SD was
consid-ered Two-group comparison was performed non-parametrically
using the Mann–Whitney U test ROC curve was done to determine
the best cut off value of the marker to determine the highest value
of sensitivity and specificity on this point The level of significance
was at p6 0.05
3 Results The 60 HCV patients age ranged between 29 and 75 years (mean 57.65 ± 8.49 years) and they were 38 males (63.3%) and 22 females (36.7%) M:F 1.7:1 The 30 matched controls age ranged between 27 and 83 years (mean 50.3 ± 17.46 years) and they were
21 males (70%) and 9 females (30%) M:F 2.3:1 32 (53.3%) patients had arthritis while the remaining 28 (46.7%) did not All the groups
in the study were homogeneous in terms of size and demographic characteristics
The laboratory data of the patient group show that ESR (49.27 ± 21.15 mm/1st h), CRP (4.40 ± 3.27 mg/L), RF (9.69 ± 12.95 IU/mL), AST (86.52 ± 102.72 U/L), ALT (68.17 ± 118.68 U/L), Albumin (2.90 ± 0.58 g/dL) and PLT (92.62 ± 45.09 103/mm3)
The results of this study showed that there was a significantly higher anti-MCV antibody level in the patients compared to the control (p < 0.001) (Table 1) There was no significant difference
as regards anti-MCV antibody levels between HCV patients with (n = 32; 53.3%) and without arthritis (n = 28; 46.7%) (Table 2) To discriminate between anti-MCV antibody values in HCV patients with and without arthritis, ROC curve revealed that the area under the curve (AUC) of anti-MCV antibody was 0.608 (95% CI 0.46–0.75,
p = 0.15); the anti-MCV antibody was not able to discriminate between HCV patients with and without arthritis (Fig 1) The HCV patients without arthritis had a significantly higher level of anti-MCV antibody than the control (p < 0.001) (Table 3) ROC curve between anti-MCV antibody values in HCV patients without arthritis and control revealed that the anti-MCV antibody AUC was 0.85 (95% CI 0.69–1, p = 0.004) When the cut-off value for anti-MCV antibody was set at 57.5 ug/L, clinical sensitivity was 80% and specificity was 80% (Fig 2)
Correlation between anti-MCV antibody and other studied parameters showed no significant relation to age, HCV disease duration, CRP, ESR, RF, AST, ALT, Albumin, platelets and HCV-RNA-PCR (Table 4)
4 Discussion
In addition to its hepatic effects, HCV is responsible for numer-ous extra hepatic manifestations (EHMs)[12] Hepatitis C–related arthritis is one of the most common EHMs of HCV infections Hepatitis C arthritis can mirror rheumatoid arthritis (RA) symp-toms[13] Consequently, HCV infection should be considered in the differential diagnosis of patients with atypical arthritis[14] The worldwide prevalence of arthritis presumed to be due to HCV infection has been reported between 2.4–45.9 million people There is no single clinical picture of arthritis in patients with HCV infection HCV-related arthritis commonly presents as rheumatoid-like polyarthritis or less commonly as mono-oligoarthritis of large joints However there is a well-defined picture of arthritis associ-ated with the presence of mixed cryoglobulinemia that consists
of an intermittent mono-or oligoarticular, nondestructive arthritis affecting large and medium-size joints[15] In an Egyptian study
on HCV patients, joint involvement was reported in 85.2% [16]
Table 1 Anti-mutated citrullinated vimentin antibody level in HCV patients and control Subjects Anti-mutated citrullinated vimentin (ug/L)
HCV patients (n = 60) 250 175–375 <0.001 Controls (n = 30) 10 5–15
HCV: Hepatitis C virus.
Please cite this article in press as: El Fedawy S et al Role of anti-mutated citrullinated vimentin antibodies in chronic hepatitis C patients and its relation to
Trang 3while arthritis was found in 22%[17]and 53.1% in other studies
[18]
Protein citrullation is involved in the pathogenesis of certain
human diseases, the best example is RA The most specific family
of RA antibodies is the antibodies directed against citrullinated
proteins (anti-CCP and anti-MCV)[19] The anti-citrullinated
pro-tein antibodies are produced locally in the inflamed synovium
and since hepatic stellate cells, which play a pivotal role in hepatic
fibrosis, contain vimentin, oxidative stress due to liver injury can
modify this vimentin which is known to undergo protein
citrulli-nation and become immunogenic stimulating the production of
anti-MCV antibody[20] The scientists hypothesized that protein
citrullination of vimentin may also occur in chronic hepatitis and
may partly explain the fibrosis seen in this disease[21]
The aim of the present study was to determine the role of
anti-MCV antibodies in chronic hepatitis C patients and its relation to
HCV associated arthritis The study included 60 patients with
pos-itive anti-HCV antibodies and HCV RNA and those with associated
arthritis were compared to those without The results of our study show that there was a significantly higher anti-MCV antibody level
in the patients compared to the control This result was in agree-ment with the results of Abdeen et al.[21] and Vassiliadis et al
[22] There was no statistically significant difference as regards anti-MCV antibody levels between HCV patients with and without arthritis This comes in accordance with Zehairy and colleagues[4]
who compared anti-MCV between HCV patients with and without arthritis (30% vs 32%, respectively) and showed no significant dif-ference In addition, Kaptanoglu and colleagues [23]investigated the diagnostic value of anti-MCV in 30 HCV infected patients, with (33%) and without arthralgia (67%), and found no significant differ-ence This implies a limited role of serum anti-MCV antibodies to discriminate between HCV patients with and without arthritis However, using the ROC curve revealed that the anti-MCV antibody would significantly discriminate between HCV patients without arthritis and the control with a sensitivity and specificity of 80% Thus the value of anti MCV antibody in diagnosing arthritis in patients infected with HCV is questionable
Table 2
Anti-mutated citrullinated vimentin antibody in HCV patients with and without
arthritis.
HCV patients (n = 60) Anti- mutated citrullinated vimentin
(ug/L) Median Range p With arthritis (n = 32) 300 200–475 0.15
Without arthritis (n = 28) 200 175–375
HCV: Hepatitis C virus.
Figure 1 ROC curve of anti-mutated citrullinated vimentin antibody between HCV
patients with and without arthritis.
Table 3
Anti-mutated citrullinated vimentin antibody in HCV patients without arthritis and
control.
Subjects Anti-mutated citrullinated vimentin
(ug/L) Median Range p Patients without arthritis (n = 28) 200 175–375 <0.001
Controls (n = 30) 10 5–15
Figure 2 ROC curve of anti-mutated citrullinated vimentin antibody between HCV patients without arthritis and control.
Table 4 Correlation between anti-mutated citrullinated vimentin antibody with various studied parameters in HCV patients.
Parameters Anti-MCV (ug/L)
Disease duration (months) 0.05 0.73
Platelet x10 3
/mm 3
Anti-MCV: Anti-mutated citrullinated vimentin, HCV: Hepatitis C virus, CRP: C-reactive protein, ESR: Erythrocyte sedimentation rate, RF: Rheumatoid factor, AST: Aspartate transaminase, ALT: Alanine transaminase, PCR: Polymerase chain reaction.
Please cite this article in press as: El Fedawy S et al Role of anti-mutated citrullinated vimentin antibodies in chronic hepatitis C patients and its relation to
Trang 4Furthermore, there was no significant correlation of the
anti-MCV antibody level with other studied paramaeters These results
coincide with those of Liu et al.[10] while Mathsson et al.[24]
found a significant correlation only between anti-MCV antibody
and the ESR
In conclusion, anti-MCV antibody is significantly increased in
HCV patients compared to control and this increase could not be
attributed to the presence of articular involvement, but may be
either the result of nonspecific reaction as other autoantibodies
detected in association with chronic HCV infection or their
presence may underlie an un-identified role in its pathogenesis
Anti-MCV antibody cannot be used as a dependable marker in
diagnosing arthritis in HCV infected patients and its estimated
value should be interpreted cautiously because HCV infection
alone can elevate anti MCV antibody titer even in the absence of
arthritis
Conflict of interest
None
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Please cite this article in press as: El Fedawy S et al Role of anti-mutated citrullinated vimentin antibodies in chronic hepatitis C patients and its relation to