Anti CCP antibody assay: a diagnostic dilemma in

World Journal of Pathology
Original Article
Open Access
Anti CCP antibody assay: a diagnostic dilemma in diagnosis of
tubercular Synovitis.
1
Saurabh Singh,2 Usha Singh, 1Abhijeet Kunwar, 2Neha Chaurasia
1Department
of Orthopedics, 2Department of Pathology, Institute of Medical Sciences, Banaras
Hindu University, Varanasi, India
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Abstract
Objective Anti-CCP antibodies assays have been reported to be a specific diagnostic marker than
rheumatoid factor in the diagnosis of rheumatoid synovitis. There may be diagnostic dilemma if anti CCP
antibody assays are also positive in cases of tubercular synovitis. In this study we look for prevalence of
anti CCP in cases of active tubercular synovitis of knee and compare it with controls.
Methods Serum levels of anti CCP antibodies were measured in 31patients of tubercular arthritis of
knee and were compared with equal number of age matched controls. Results: 38.7% of tubercular
arthritis patients showed positive results on serum antiCCP antibody assay and the mean of anti CCP
levels in patients of tubercular arthritis was more than that in the control group
Discussion: Anti CCP assay for diagnosis of rheumatoid synovitis may give false positive results in
patients of tubercular arthritis
Conclusion Test for anti CCP antibody is positive in many patients of tuberculous synovitis.
Key words Tuberculosis, rheumatoid arthritis, false positive
Introduction
rheumatoid factor in their serum, in 40% cases
[5].
The global incidence of tuberculosis (TB) is around
8.8 million and prevalence 14 million as per World
In a recent study, anti-CCP antibody positivity has
Health Organization reports and of this 1%–3% is
been reported in 32% of patients with active
skeletal
disease
[1].
TB
arthritis
is
pulmonary TB [6]. With increasing prevalence of
characteristically monoarticular [2] and most
TB in developed nations and their continued
often affects the spine and weight-bearing joints
presence in developing nations this may create
such as the knee and hip. In spite of monoarthritis
diagnostic dilemma in establishing a case of mono
being the most common presentation in weight
or pauciarticular arthritis as that of tuberculosis
bearing joints oligo or polyarthitis is not a rare
or of rheumatoid arthritis.
presentation resembling the clinical picture of
Anti-CCP antibodies have been reported to be a
spondyloarthropathies [3] or rheumatoid arthritis
novel and more specific diagnostic marker than
(RA) [4]. Patients of tuberculosis may have
rheumatoid factor (RF) in the diagnosis of RA.
Address for correspondence and reprint requests to:
Antibodies that are formed against CCP primarily
Dr.Abhijeet kunwarSenior ResidentDept.of OrthoI.M.S.,B.H.U.
belong to the immunoglobulin G class and are
Varanasi-221005
97% specific for RA [7, 8]. With emerging
Email: [email protected]
© 2014 Singh S et al. Licensee Narain Publishers Pvt. Ltd.
evidence linking anti ccp positivity with
(NPPL)
pulmonary tuberculosis there is need to further
Submitted: Wednesday, April 2, 2014 Accepted: Saturday,
April 26, 2014 Sunday, April 27, 2014
investigate the association of anti ccp positivity
with various forms of tuberculosis. In this study
38
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World J Pathol 2014;3:38-44
Tubercular Synovitis
Table 1: shows the questionnaire and criteria used to rule out possibility of rheumatoid arthritis in
suspected cases of tubercular arthritis (American College of Rheumatology (ACR)/European
LeagueAgainst Rheumatism (EULAR) 2010 [9]).
Clinical characteristics
Fever duration [mean]
Mean age [in years]
Arthralgia in multiple large
joints[ more than 2 joints]
Myalgia
Small joint arthritis[ based
on clinical and radiological
examination findings of hand
and feet]
Mucocutaneous
symptoms, siccasymptoms ,
spontaneous abortion, history
of thrombosis, and familial
history
of
autoimmune
diseases.
ACR/EULAR classification
criteria - scores of 6 or more
Patients of tubercular
arthritis[cases] [n=31]
3.4 months
43.8
3.2%
Associated pulmonary
tuberculosis[ based on
symptoms, clinical and
radiological examination
we intend to study prevalence of anti CCP
positivity in cases of active TB arthritis of knee
and compare it with the prevalence in healthy
controls.
Patients and Method
31 patients (20 males and 11 females) of newly
diagnosed active TB arthritis of knee (29 unilateral
and 2 bilateral knee diseases) were included in
the study. Provisional diagnosis of TB arthritis was
made on the basis of history of fever, chronic
knee pain, clinical examination and plain
radiography findings. All patients were subjected
to open synovial biopsy and only patients who
proved
positive
for
tuberculosis
on
histopathological examination were included in
the study.
Serum sample for anti ccp was taken upon
histopathological confirmation of TB arthritis.
Only newly diagnosed patients of tubercular
39
Healthy controls [n=62]
44.5
-
6.4%
-
-
-
-
-
-
2
-
arthritis of knee were included and patients on
prior anti tubercular drug therapy were excluded
from the study.
The kit used for the test was Genesis Diagnostics’
(Cambridgeshire, UK, www.elisa.co.uk) EDRA
Genesis CPA kit. This is an ELISA [Enzyme linked
immune sorbent assay] test and the steps of
handling of serum sample and of the test were
followed as per the instructions of the
manufacturer of the kit. In this test a value of
more than 6.25 is considered to be positive.
A questionnaire was used to determine the
presence of rheumatological symptoms like pain
in other joints, myalgia, rash, mucocutaneous
symptoms, family history of autoimmune
diseases.
Along
with
this,
ACR/EULAR
classification criteria (2010) [9] was used to rule
out the possibility of RA in the cases and control
groups. According to the ACR/EULAR 2010 criteria
a score of more than or equal to 6 out of 10 is
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World J Pathol 2014;3:38-44
needed for the patients to be termed as of
rheumatoid arthritis [9].
Statistical analysis
Statistical analysis was performed by the SPSS 17
software, using Student’s t test and a Chi square
test to compare antibody titres or positivity rate,
respectively, between patients with TB and
controls. Pearson correlation coefficients were
used to study the relationship between clinical
measures and the levels of anti-CCP. A value of
p<0.05 was considered significant.
Results
Table 1 summarizes the results of the clinical
characteristics of patients with TB and healthy
controls.
The patients had a mean duration of fever of 3.4
months, 74.19% had fever. Only a small minority
had symptoms such as arthralgia [3.2%], myalgias
[6.4%]. None of the patients had signs typical of
rheumatoid arthritis such as arthritis, morning
stiffness or rheumatoid nodules or could get a 6
or higher score on ACR/EULAR2010 classification
criteria [9].
Serum levels of anti-CCP
The mean (SD) levels of anti-CCP were
significantly increased in patients with TB arthritis
in comparison with controls: [9.95[10.81] V
4.09[0.83])[p value<0.005]. Serum levels above
the upper normal limits (6.25 IU) were found in
12/31 (38.7%) patients in comparison with 1/47
(2.1%). Gupta et al determined the sensitivity and
specificity of use of anti ccp2 antibody assay in 63
Indian patients and found Fifty-four of 63 RA
patients (85.71%) were positive for anti-CCP,
while 9 patients tested negative for anti-CCP
antibodies. Their study found a sensitivity of 85%
and a specificity of 90.19% in regards to the use of
anti-CCP antibodies assay in patients with
synovitis and joint pain to correctly identify
rheumatoid arthritis [10].
40
Singh S et al.
Discussion
Antibodies recognizing cyclic citrullinated
peptides are highly specific for RA [11]. The
specificity for RA has been shown to be up to 98%
in comparison with 0–1% of healthy controls and
2–5% of disease controls. Anti-cyclic citrullinated
proteins (anti-CCP) are present early in the
disease process and may even pre-date the onset
of RA by many years [12].
In 1964, Nienhuis and Mandema described an
autoantibody they called antiperinuclear factor.
Detected by indirect immunofluorescence test on
human buccal mucosa cells, antiperinuclear factor
recognized antigens present in keratohyalin
granules surrounding the nucleus [13].
Antiperinuclear factor was present in up to 90%
of established RA patients, with 73–99%
specificity [14]. Young and colleagues later
detected antikeratin antibodies using indirect
immunofluorescence on cryosections of rat
esophagus [15]. The reported sensitivity of the
antikeratin assay in RA patients was 36–59% and
the specificity was 88–99% [14]. Despite the high
specificity for RA, these tests were not widely
used because of difficulty in standardization of
natural substrates and arbitrary interpretation of
the indirect immunofluorescence pattern. In
1995, Sebbag and colleagues demonstrated that
both of these antibodies belonged to a family of
autoantibodies directed against citrullinated
filaggrin, an epithelial cell protein [16].
Citrullination is a posttranslational modification of
arginine to citrulline by the enzyme peptidyl
arginine deiminase. This process occurs naturally
during
inflammation,
apoptosis,
and
keratinization [17]. Thus it can be postulated that
anti CCP antibody may be present in other
inflammatory disorders. Although filaggrin is not
present in the synovium [18], several citrullinated
proteins, including fibrinogen and fibronectin, are
present in RA synovium, and other citrullinated
epitopes have been identified as targets of highly
RA-specific autoantibodies [19-21]. The first
commercially available ACPA assay (firstgeneration CCP [CCP-1]) was developed by EuroDiagnostica (Arnhem, The Netherlands) and was
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World J Pathol 2014;3:38-44
used in early studies (2000 to 2001). This ELISAbased test employed a single CCP derived from
filaggrin. The assay detected autoantibodies in
53% of established RA patients, with 96%
specificity [22]. Peptide libraries were then
screened for better epitopes. Since 2000, secondgeneration CCP (CCP-2) and third-generation CCP
(CCP-3) assays have been developed. The
compositions of many new CCP-3 peptides are
not yet publicly available because patents are
pending [23]. We in this study have used anti ccp2
assay.
Anti CCP antibody assays are able to predict the
development of RA in healthy subjects [24], and
are prognostic markers of erosive disease
progression [25]. It has also been shown that this
marker system can help in discriminating between
RA and other forms of erosive arthritis that can
simulate rheumatoid arthritis [26]. Shankar et[27]
al in their study of 211 patients with established
RA concluded that anti CCP-2antibodies were the
most important factor in predicting erosive
disease. They were of the opinion that these
antibodies were strong predictors of erosive
disease in both sero positive and sero negative RA
and had an additional role in predicting
cumulative radiological damage over and above
that predicted by rheumatoid factor. Anti‐CCP
antibodies are rarely detectable in other diseases,
and in these cases usually with low titers [28].
There are many differential diagnosis that have to
be kept in mind while labeling a patient as of
rheumatoid arthritis especially when the disease
in monoarticular or pauciarticular involving the
large joints. Amongst them one is early stage of
TB arthritis.
TB arthritis is commonly is monoarticular [2] and
most often affects the spine and weight-bearing
joints such as the knee and hip. The mode of
transmission is hematogenous from visceral foci
such as the lung or kidneys [1]. Articular disease
often starts as a synovitis progressing to arthritis,
with demineralization, marginal erosions, and
ultimate joint destruction [29]. While the time
period from synovitis to arthritis and erosions
may be long, progression to joint destruction can
41
Tubercular Synovitis
be rapid, particularly in weight-bearing joints.
Thus there is a need for early diagnosis of the
disease and institution of appropriate treatment
[30].
Patients with TB can exhibit various forms of
arthropathy, which in some cases may mimic RA
[31]. Some of these patients' diseases may mimic
early rheumatoid arthritis and may be difficult to
diagnose. Thus, anti-CCP–positive test results in
these patients can be misleading [31].
In a recent study, the prevalence of anti-CCP
antibodies was shown to be 37% in Japanese
patients with active pulmonary TB [32]. Elkayam
et al [6] compared anti-CCP antibody positivity
and Immunoglobulin M (IgM) RF status in 47
patients with active pulmonary TB infection and
39 healthy controls. Anti-CCP titers were above
normal in 32% of the patients with active TB
infection, while the rate was only 2.6% in
controls.Mori et al [33] in their study, we found
positivity rate of anti-CCP2in the cases of active
lung tuberculosis to be 6.7% (six of 89 patients)
and3.4% of these patients were strongly positive.
They found the prevalence of anti-CCP2 in healthy
individuals to be 0.4%.
In our study the prevalence of anti ccp2 antibody
positivity in cases of active tubercular arthritis
was found to be 38.7% and that in healthy
controls to be 2.1%.
Anti ccp antibody assay has also been found to be
positive in other disease also. It has also been
shown that prevalence of anti-CCP3 in patients
with leprosy, another disease caused by
mycobacterial infection is 3.1% [34]. It has also
been reported that anti‐CCP antibodies (using a
CCP2 test) can be detected in 9% of patients with
autoimmune hepatitis‐1, in absence of
recognizable rheumatoid arthritis overlap, and in
some cases with high titers, comparable to those
observed in rheumatoid arthritis [35].
The mechanism of production of anti ccp
antibody in patients of TB is still not very evident.
The mechanism cited in literature is as follows.
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World J Pathol 2014;3:38-44
Citrulline, a non-standard amino acid, is not
incorporated into proteins during translation;
citrullinated proteins are generated by
posttranslational conversion of protein-contained
arginine
residues
to
citrulline
by
peptidylargininedeiminase enzyme. Citrullinated
proteins are present in a wide range of
inflammatory tissues, with little to no expression
in non inflammatory tissues, suggesting that the
citrullination of cellular proteins is not specific to
RA but is rather a common phenomenon in
various inflammatory conditions [36-38].
Citrullination may occur at sites of inflammation
in patients with active TB, even without arthritis,
and its occurrence may be related to the degree
of inflammation. It is possible, therefore, that
anti-citrullinated antibodies maybe generated in
response to citrullination in some TB patients
without arthritis [33]. Kakumanu et al [32]
showed that many anti-CCP-positive sera
obtained from patients of pulmonary tuberculosis
also react with a corresponding non-citrullinated
argininecontaining peptide (CAP) and that high
anti-CCP:anti-CAP ratios (>2.0) were seen far
more commonly in anti-CCP–positive RA patients
than in anti-CCP–positive TB patients (94% versus
22%). They also revealed that the anti-CCP
reactivity, in sera from the RA patients is nearly
completely inhibited by preincubation with CCP
but this does not happen in sera from
tuberculosis patients [32]. These data suggest
that anti-CCP in sera from RA patients is specific
to CCP, whereas the anti-CCP reactivity seen in
the sera of tuberculosis patients may be citrullineindependent [33].
Thus in the light of these new revelations the
validity of anti ccp antibody assay in diagnosis of
RA has come into question. With increasing
prevalence of TB in developed nations and
continued presence of the disease in the
developing nations, the use of anti ccp antibody in
diagnosis of RA must also take into account other
clinical and laboratory features of rheumatoid
arthritis. Early onset TB arthritis should be kept as
a differential and must be ruled out systematically
in patients presenting with large joint mono or
42
Singh S et al.
pauciarticular synovitis with positive anti ccp
antibody assay.
Conclusion
Anti ccp antibody assay may be false positive in
many patients of tubercular synovitis. Patients
presenting with mono or pauciarticular pain of
large joints with positive anti ccp antibody assay
have to be investigated to rule out the possibility
of early stage of tubercular arthritis before
labeling them as of rheumatoid arthritis. Low
threshold for suspicion and thorough investigative
workup is essential for early diagnosis,
appropriate treatment and good outcome in
tubercular arthritis.
Authors Contributions
SS: Designed the study and clinical diagnosis
US: Laboratory investigations done under her
supervision, writing of laboratory part
AK: Clinical diagnosis and assisted in manuscript
compilation
NC: Assisted in laboratory investigations and
drafting of manuscript
Conflict of interest:
The authors declare that there is no conflict of
interests
Acknowledgements
None
Ethical considerations
The study was approved by the Institute Ethics
Committee, written informed consent was
obtained from all the subjects participating in the
study.
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