Patients With Pulmonary Tuberculosis Are Frequently Positive for Anti–Cyclic Citrullinated Peptide Antibodies, but Their Sera Also React With Unmodified Arginine-Containing Peptide potx

ARTHRITIS & RHEUMATISM
Vol. 58, No. 6, June 2008, pp 1576–1581
DOI 10.1002/art.23514
© 2008, American College of Rheumatology
Patients With Pulmonary Tuberculosis Are Frequently Positive
for Anti–Cyclic Citrullinated Peptide Antibodies, but Their Sera
Also React With Unmodified Arginine-Containing Peptide
Prasanthi Kakumanu,
1
Hajime Yamagata,
2
Eric S. Sobel,
1
Westley H. Reeves,
1
Edward K. L. Chan,
1
and Minoru Satoh
1
Objective. The anti–cyclic citrullinated peptide
(anti-CCP) enz yme-linked immunosorbent assay
(ELISA) has high sensitivity and specificity for rheu-
matoid arthritis (RA). However, detection of anti-CCP
in patients with active pulmonary tuberculosis (TB) has
recently been reported. To determine whether this ac-
tivity was specific for the citrullinated residue, the
specificity of anti-CCP–positive sera for CCP versus
that for unmodified arginine-containing peptide (CAP)
was examined in patients with TB and compared with
that in patients with RA.
Methods. Anti-CCP and anti-CAP in sera from

patients with pulmonary TB (n ؍ 49), RA patients (n ؍
36), and controls (n ؍ 18) were tested by ELISA. Sera
were available at diagnosis from most TB patients. All
TB patients were treated with a combination of 2–4
antibiotics for at least 6 months, and sera were collected
over time.
Results. Anti-CCP was found in 37% of TB pa-
tients and in 43% of RA patients. CAP reactivity was
more common in TB than in RA. 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%). Anti-CCP was
inhibited by CCP peptide in sera from RA patients, but
not in sera from TB patients. A slight increase in
anti-CCP was common after initiating treatment for TB,
although the anti-CCP level decreased after 1–2 months.
Conclusion. Anti-CCP is frequently present in
patients with active TB. However, many anti-CCP–
positive TB sera also reacted with CAP, and anti-CCP:
anti-CAP ratios in TB sera were low. Anti-CCP:anti-
CAP ratios should be useful clinically for distinguishing
CCP-specific reactivity seen in RA from reactivity with
both CCP and CAP frequently seen in pulmonary TB.
Anti–cyclic citrullinated peptide (anti-CCP) us-
ing a peptide of filaggrin has been used extensively as a
new serologic marker of rheumatoid arthritis (RA) (1,2).
Many studies have confirmed that anti-CCP enzyme-
linked immunosorbent assay (ELISA) is as sensitive as
rheumatoid factor (RF) and much more specific for RA
among various rheumatic diseases (2). However, anti-

CCP in other diseases has been less well studied. Pa-
tients with certain infectious diseases, such as hepatitis C
and tuberculosis (TB), can present with arthritis and
frequently also have serum RF, making it difficult to
distinguish infectious disease–related arthritis from RA.
Thus, the utility of anti-CCP testing under these clinical
circumstances is important. Studies in patients with
hepatitis C viral infection showed the absence of anti-
CCP, in contrast to frequent RF positivity (3). However,
a recent study showed the presence of anti-CCP in 32%
of patients with active pulmonary TB (4).
Patients with TB can exhibit various forms of
arthropathy, including tuberculous arthritis and reactive
arthritis (5). Some of these patients’ diseases may mimic
early RA and may be difficult to diagnose. Thus, anti-
CCP–positive test results in these patients can be mis-
leading. Early studies showed that anti-CCP antibodies
in RA patients are specific for citrullinated peptide and
do not react with unmodified peptide (1). However, the
Supported by the NIH (grants R01-AR-40391 and M01-R-
00082) and the Lupus Foundation of America.
1
Prasanthi Kakumanu, MD, Eric S. Sobel, MD, PhD, Westley
H. Reeves, MD, Edward K. L. Chan, PhD, Minoru Satoh, MD, PhD:
University of Florida, Gainesville;
2
Hajime Yamagata, MD, PhD:
National Hospital Organization, Murayama Medical Center, Musashi-
Murayama, Tokyo, Japan.
Address correspondence and reprint requests to Minoru

Satoh, MD, PhD, Division of Rheumatology and Clinical Immunology,
University of Florida, PO Box 100221, Gainesville, FL 32610-0221.
E-mail:
Submitted for publication October 11, 2007; accepted in
revised form February 25, 2008.
1576
majority of clinical studies on anti-CCP are based on
commercial anti-CCP ELISA kits and do not use an
unmodified peptide as a negative control (2). In the
present study, the specificity of anti-CCP–positive sera
for CCP versus unmodified arginine-containing peptide
(CAP) was examined in patients with TB and compared
with that in patients with RA.
PATIENTS AND METHODS
Patients. Sera were obtained from Japanese patients
with pulmonary TB (n ϭ 49) or RA (n ϭ 36) or from controls
(n ϭ 18) at the National Hospital Organization, Murayama
Medical Center, Musashi-Murayama, Tokyo, Japan. In the
majority of patients with TB, the diagnosis was confirmed by
culture for Mycobacterium tuberculosis, and all were treated
with a combination of 2–4 antibiotics (streptomycin, isoniazid
[INH], rifampin [RIF], ethambutol, para-aminosalicylic acid)
for at least 6 months. None of the patients had atypical
Mycobacterium. The initial sera from 36 TB patients were
obtained before or within 1 month of treatment. In 6 TB
patients, the first serum sample was obtained after 2–6 months
of treatment. Detailed information was not available for 7 TB
patients. Serial monthly sera were available from 25 patients
with TB. The protocol was approved by the Institutional
Review Board.

Anti-CCP/anti-CAP ELISA. CCP (cfc1-cyc; amino ac-
ids 306–324 of filaggrin, where arginine at position 312 is
replaced with citrulline) and CAP (cf0-cyc; same peptide with
arginine at position 312) peptides (1) were synthesized, cy-
clized with Tl(CF
3
CO
2
)
3
in dimethylformamide/anisole (19:1),
and purified using high-performance liquid chromatography at
the Interdisciplinary Center for Biotechnology Research Pro-
tein Core Facility of the University of Florida. ELISA was
performed as described elsewhere (6). Briefly, half of the
microtiter plate wells (Immobilizer; Nunc, Naperville, IL) were
coated with 2
␮
g/ml CCP and the other half with CAP in 0.1M
NaH
2
PO
4
, pH 9.0, at 4°C overnight. After blocking with 0.5%
bovine serum albumin in NET (50 mM Tris, pH 7.5, 0.15M
NaCl, 2 mM EDTA)/0.3% Nonidet P40 (NP40) (blocking
buffer), wells were incubated with 1:500-diluted sera or the
serially diluted high-titer anti-CCP–positive standard in the
blocking buffer for 2 hours at 22°C. After washing 3 times with
Tris buffered saline–Tween 20 (20 mM Tris, pH 7.5, 150 mM

NaCl, 0.1% Tween 20), wells were incubated with alkaline
phosphatase– conjugated goat anti-human IgG (1:1,000,
␥
-chain specific; Southern Biotechnology, Birmingham, AL) in
blocking buffer, washed, and developed.
The optical density at 405 nm (OD
405 nm
) of each
sample was converted into units using the SoftMax Pro 4.7
program (Molecular Devices, Sunnyvale, CA), with 4-para-
meter analysis. The standard curve was established by arbi-
trarily defining the OD from a 1:312,500-diluted standard
serum as 1 unit and applying units to each dilution so that the
units correlated with the amount of antibodies as follows: 1:500
dilution, 625 units; 1:2,500 dilution, 125 units; 1:12,500 dilu-
tion, 25 units; 1:62,500 dilution, 5 units; 1:312,500 dilution, 1
unit; and 1:1,562,500 dilution, 0.2 units. Both anti-CCP and
anti-CAP units were interpolated from the same anti-CCP
standard curve. The cutoff values for anti-CCP positivity (1.7
units) and anti-CCP:anti-CAP ratios (2.0) were determined
based on the receiver operating characteristic curves compar-
ing RA patients and controls.
Inhibition of ELISA reactivity with CCP or CAP
peptide, and effects of different concentrations of NaCl on
antibody binding. Inhibition of ELISA reactivity with CCP or
CAP was evaluated by incubating diluted serum with CCP
or CAP peptide and then applying it to wells coated with
CCP or CAP. Each serum was diluted (1:125–1:2,500; final
concentration 1:250–1:5,000) so that the reactivity was at the
low linear range of the standard curve (10–50 units) for

sensitive detection of inhibition. CCP or CAP peptide (serially
diluted 1:10, from 5,000 ng/ml to 0.5 ng/ml) in blocking buffer
or buffer alone and appropriately diluted sera were mixed at a
1:1 ratio. After incubation for 1 hour at 22°C, 100
␮
lofthe
mixture was added to the wells coated with CCP or CAP,
followed by secondary antibodies. OD
405 nm
values were con
-
verted into anti-CCP or anti-CAP units. The percentage
inhibition of each sample was calculated as 100 ϫ (units of the
serum incubated with buffer Ϫ units of the serum incubated
with an inhibitor)/(units of the serum incubated with buffer).
In other experiments, the effects of different concen-
trations of NaCl on antibody binding to CCP or CAP were
evaluated. Following incubation with serum samples and wash-
ing, wells were incubated for 30 minutes with NET/NP40
containing 0.15M, 0.375M,or0.5M NaCl, and the protocol was
then continued as above.
RESULTS
Anti-CCP and anti-CAP ELISA. Anti-CCP (Ͼ1.7
units) was frequently present in TB patients (37%) and
RA patients (43%), consistent with the previous report
(4). Although the levels of anti-CCP in RA patients
appeared to be generally higher than those in TB
patients (mean Ϯ SD 31.0 Ϯ 99.8 units versus 4.1 Ϯ 8.6
units) and the percentage of high-positive values (Ͼ10
units) was greater in RA patients (22% versus 10%),

neither of the differences was statistically significant.
High anti-CAP levels (Ͼ10 units) were found only in TB
patients (4%). The reactivity of sera from RA patients
was specific for CCP, and serum from only 1 RA patient
was also reactive with CAP (P Ͻ 0.0001 for anti-CCP
reactivity versus anti-CAP reactivity in RA patient sera).
In marked contrast, sera from patients with TB reacted
to CCP and CAP (Figure 1A). Moreover, while the
frequency of anti-CCP in RA patients (43%) and TB
patients (37%) was similar, anti-CAP was more fre-
quently present in TB patients than in RA patients (27%
versus 3%; P Ͻ 0.005 by Fisher’s exact test) (Table 1).
Since anti-CCP in RA patients appeared to be
specific for CCP while anti-CCP in TB patients also
reacted with CAP, anti-CCP:anti-CAP ratios were cal-
culated to test whether this parameter could be used
ANTI-CCP IN TUBERCULOSIS 1577
diagnostically to distinguish citrulline-dependent anti-
CCP reactivity in RA from citrulline-independent anti-
CCP reactivity in TB. High anti-CCP:anti-CAP ratios
(Ͼ2.0) were seen far more commonly in anti-CCP–
positive RA patients than in anti-CCP–positive TB
patients (94% versus 22%; P Ͻ 0.0001) (Figure 1B and
Table 1).
Time course of anti-CCP antibodies. Certain
drugs that are commonly used to treat TB, such as INH
and RIF, are known to be associated with drug-induced
lupus and the production of antinuclear and antihistone
antibodies. The majority of TB patients (36 of 49) had
sera available for testing that were obtained before or

within 1 month of treatment. These sera were still
positive for anti-CCP, indicating that the production of
anti-CCP was related to TB and was not the result of
treatment. However, to address the question of whether
anti-CCP levels increased during treatment, we analyzed
sequential sera that were available from 25 patients with
TB. Among the 8 TB patients who were anti-CCP
positive (Ͼ1.7 units) and the additional 6 TB patients
with borderline anti-CCP positivity (1.2–1.7 units) who
were tested over time, a transient increase of anti-CCP
after initiating treatment was common (11 of 14 patients
had an increase after 1 month, 2 of 11 patients had an
increase at 2 months). However, in 9 patients examined
Figure 1. A, Levels of anti–cyclic citrullinated peptide (anti-CCP) antibodies compared with anti–unmodified arginine-containing peptide
(anti-CAP) antibodies in patients with rheumatoid arthritis (RA), patients with tuberculosis (TB), and in healthy controls. Anti-CCP and anti-CAP
antibodies in sera from RA patients (n ϭ 37), TB patients (n ϭ 49), and healthy controls (n ϭ 18) were tested by enzyme-linked immunosorbent
assay (ELISA). Optical densities were converted into units. The cutoff value of anti-CCP and anti-CAP was 1.7 units (shaded area). Horizontal bars
indicate the median. P values for anti-CCP reactivity versus anti-CAP reactivity were obtained by Wilcoxon’s matched pairs test. NS ϭ not
significant. B, Anti-CCP:anti-CAP ratios in anti-CCP–positive (Ͼ1.7 units) sera from patients with RA and TB. The ratios were high (Ͼ2.0) in 94%
of RA patients, but in only 22% of TB patients. P values were obtained by Mann-Whitney U test. The cutoff value of the anti-CCP:anti-CAP ratio
was 2.0 (shaded area). Horizontal bars indicate the median. C, Changes in anti-CCP levels in patients with TB over time. Sera obtained monthly from
14 TB patients (8 anti-CCP positive, 6 borderline anti-CCP positive) were tested by anti-CCP ELISA. A transient increase in anti-CCP levels after
initiation of treatment was common (11 of 14 patients had an increase after 1 month, 2 of 11 patients had an increase at 2 months). However, in
9 patients examined for 2 months or more, the anti-CCP level decreased after 1–2 months.
Table 1. Anti-CCP and anti-CAP levels and anti-CCP:anti-CAP
ratios in RA patients, TB patients, and controls*
RA patients
(n ϭ 37)
TB patients
(n ϭ 49)

Controls
(n ϭ 18)
Anti-CCP Ͼ1.7 units 43 37 6
Anti-CAP Ͼ1.7 units 3† 27 6
Anti-CCP:anti-CAP ratio
Ͼ2.0 (all subjects)
59‡ 12 17
Anti-CCP:anti-CAP ratio
Ͼ2.0 (subjects with
anti-CCP Ͼ1.7 units)
94‡ 22 0
* Values are the percentage of patients or controls. Anti-CCP ϭ
anti– cyclic citrullinated peptide; anti-CAP ϭ anti–unmodified
arginine-containing peptide; RA ϭ rheumatoid arthritis; TB ϭ tuber-
culosis.
† P Ͻ 0.005 versus TB patients, by Fisher’s exact test.
‡ P Ͻ 0.0001 versus TB patients, by Fisher’s exact test.
1578 KAKUMANU ET AL
for 2 months or more, the anti-CCP level decreased after
1–2 months (Figure 1C). In addition, none of the
remaining 11 patients who were initially anti-CCP
negative became anti-CCP positive (Ͼ1.7 units) after
treatment.
Inhibition of ELISA reactivity using CCP or CAP
peptide and the effects of different concentrations of
NaCl on antibody binding. We examined whether solu-
ble CCP or CAP peptides could inhibit antibody binding
to CCP or CAP using 5 sera from RA patients (all were
anti-CCP positive and anti-CAP negative) and 4 sera
from TB patients (all were positive for anti-CCP and

anti-CAP). In sera from all 5 RA patients, antibody
binding to CCP was nearly completely (87.8–99.8% at
2,500 ng/ml CCP) inhibited in a dose-dependent manner
(Figures 2A–D). CAP did not have clear effects on
anti-CCP binding in sera from 3 patients (Figures 2A–
C), consistent with a lack of cross-reactivity of anti-CCP
and anti-CAP in these sera. However, in addition to
nearly complete inhibition of anti-CCP binding by CCP,
CAP also showed weak but reproducible inhibition of
anti-CCP binding in sera from 2 patients (15.3% and
22.2% inhibition) (Figure 2D). These 2 patients were
classified as anti-CAP negative (Ͻ1.7 units) in the
screening; however, their anti-CAP antibodies were at
detectable levels, suggesting that they might have low
levels of antibodies to CAP. Both CCP and CAP weakly
(16.5–25.6%) inhibited anti-CAP binding in sera from
these 2 patients (Figure 2D).
In sera from all 4 TB patients with anti-CCP and
anti-CAP positivity that were tested, inhibition by either
peptide was not detected (Figures 2E and F). Unlike the
reactivity of certain low-affinity antibodies, anti-CCP or
anti-CAP reactivity was not affected significantly (Ͻ5%)
by incubation of wells with higher concentrations of
NaCl (0.375M or 0.5M) (data not shown), suggesting
that these interactions are of relatively high avidity.
DISCUSSION
In the present study, anti-CCP was detected in
37% of Japanese patients with active pulmonary TB,
similar to findings in a previous study from Israel, which
showed that 32% of patients with active TB were

anti-CCP positive (4). There are several situations in
which anti-CCP positivity associated with TB may mis-
lead or confuse clinical judgments on the diagnosis and
treatment of arthritis. First, monarthritis or oligoarthri-
Figure 2. Inhibition of antibodies to CCP or CAP by preincubation with CCP or CAP peptide. Sera from anti-CCP–positive RA patients (A–D)or
anti-CCP–positive and anti-CAP–positive TB patients (E and F) were incubated with serially diluted CCP or CAP peptide and then added to wells
coated with CCP or CAP (4 sets of data for each sample). Anti-CAP reactivity was undetectable or too weak for reliable calculation of the percentage
inhibition in samples represented in A–C; therefore, anti-CAP data are not shown. The anti-CAP value in the sample represented in D was below
the cutoff level; however, it was still considered the level at which the percentage inhibition could be calculated. The optical density value at 405 nm
in each sample was converted into units as described in Patients and Methods. The percentage inhibition of each sample was calculated as 100 ϫ
(units of the serum incubated with buffer – units of the serum incubated with an inhibitor)/(units of the serum incubated with buffer). See Figure
1 for definitions.
ANTI-CCP IN TUBERCULOSIS 1579
tis caused by Mycobacterium can mimic synovitis seen in
early RA (7,8). Tuberculous arthritis used to be consid-
ered to predominantly affect weight-bearing joints such
as the hip and knee. However, changing clinical charac-
teristics with more frequent involvement of wrist and
other peripheral joints have been reported (7). Second,
patients with Mycobacterium infection can exhibit non-
infectious reactive polyarthritis, known as Poncet’s dis-
ease or tuberculous rheumatism (5). Thus, a patient
could be misdiagnosed as having early RA based on
polyarthritis and anti-CCP positivity. A third situation
arises when a patient with RA contracts or experiences
a reactivation of a TB infection and develops increas-
ing levels of anti-CCP and signs of inflammation, such
as fever, a higher erythrocyte sedimentation rate, or a
higher C-reactive protein level, and these findings are
mistakenly attributed to an RA disease flare. Biologic

agents that inhibit tumor necrosis factor
␣
have rapidly
become a part of standard therapy in RA, but they are
associated with an increased risk of developing, or
having a relapse of, Mycobacterium infection (9).
Whether nonpulmonary TB such as isolated tu-
berculous arthritis or an atypical Mycobacterium infec-
tion can also induce anti-CCP will need to be evaluated
in future studies. The effects of preventive vaccination
with BCG also need to be considered. In many Asian
countries, including Japan, BCG vaccination is manda-
tory in childhood when the skin test for purified protein
derivative (PPD) yields a negative result. Thus, positive
PPD skin test results can be seen in high frequency
among these populations, making the diagnosis of active
TB more difficult (10). The incidence of TB is also much
higher in Japan than in the US. However, the percentage
of anti-CCP positivity in normal individuals or in pa-
tients with diseases other than RA among Japanese
individuals does not appear to be higher than that in the
US or in European countries (ref. 11 and the present
study), suggesting that BCG vaccination during child-
hood does not cause long-lasting anti-CCP positivity.
However, it is not known whether preventive BCG vac-
cination can cause a transient increase in anti-CCP.
Intravesicular BCG immunotherapy has been used
worldwide in patients with bladder cancer (5,12). Whether
these patients develop anti-CCP will also need to be
evaluated, because the chronic granulomatous in-

flammation in the bladder after BCG therapy is quite
different from the inflammation arising from preventive
BCG vaccination. Reactive arthritis following BCG im-
munotherapy is well described (12), and if anti-CCP is
induced, it could also mislead diagnosis.
The mechanism of induction of anti-CCP in TB
or even in RA is not known. However, it does not appear
to be the result of treatment, as is seen for antihistone
antibodies in drug-induced lupus. The detection of IgG
anti-CCP antibodies before starting therapy and the
reduction of anti-CCP levels while continuing treatment
support this interpretation. Anti-CCP in TB may be
induced and maintained by the immune response to
chronic granulomatous inflammatory tissue rather than
by the immune response directed at live Mycobacterium,
because anti-CCP levels in patients with TB do not drop
rapidly after treatment is started (Figure 1C). Both
hepatitis C and TB patients’ sera have RF, but the
difference in the inflammatory process may explain the
absence of anti-CCP (3) in patients with hepatitis C.
Various cellular proteins are citrullinated during
apoptosis (13), and protein citrullination is a process
associated with various inflammatory conditions regard-
less of the diagnosis (14), suggesting that inflammatory
tissue and apoptotic cells in TB granuloma likely contain
citrullinated proteins as well. Thus, the citrullinated
proteins in inflammatory tissue may play a role in the
development of anti-CCP in TB. Nevertheless, the pat-
tern of host response to citrullinated versus uncitrulli-
nated peptide in RA versus TB is quite different:

anti-CCP in RA is specific for CCP, whereas anti-CCP in
TB reacts with both CCP and CAP. The poor capability
of liquid-phase CCP or CAP to cross-inhibit the reactiv-
ity of sera from patients with TB compared with sera
from patients with RA (Figure 2D) may be due to the
presence of low-avidity antibodies or to the differences
between epitopes expressed on solid-phase peptides
bound to the plastic surface (considered partially dena-
tured) and epitopes expressed on inhibitors in liquid
phase.
Thus, anti-CCP–positive sera can be classified
into 3 categories: 1) sera that have anti-CCP but little
anti-CAP (as in most RA patients), 2) sera that have
antibodies that bind to CCP and CAP but are not
polyreactive, and 3) sera with polyreactive antibodies
that bind to CCP and CAP. A recent study showed that
anti-CCP in patients with autoimmune hepatitis is often
citrulline independent and suggested that anti-CCP in
nonrheumatic diseases should be interpreted with care
(15). The present data on anti-CCP in pulmonary TB
support that interpretation.
In summary, anti-CCP is frequently present in
patients with active TB, and this may cause confusion
and clinical misjudgment in the diagnosis and treatment
of patients with RA and/or TB. However, many anti-
CCP–positive TB sera also reacted with CAP, and
anti-CCP:anti-CAP ratios in TB sera were low, very
1580 KAKUMANU ET AL
different findings from those in RA sera. Determination
of anti-CCP:anti-CAP ratios or performance of inhibi-

tion ELISAs using CCP should be useful for distinguish-
ing the CCP-specific reactivity seen in RA sera from the
reactivity to both CCP and CAP seen in TB sera.
AUTHOR CONTRIBUTIONS
Dr. Satoh had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Kakumanu, Yamagata, Satoh.
Acquisition of data. Kakumanu, Yamagata, Satoh.
Analysis and interpretation of data. Kakumanu, Yamagata, Sobel,
Reeves, Chan, Satoh.
Manuscript preparation. Kakumanu, Yamagata, Sobel, Chan, Satoh.
Statistical analysis. Satoh.
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