Download Periodontal pathogens participate in synovitis in patients with

Rheumatology 2015;54:2257–2263
doi:10.1093/rheumatology/kev274
Advance Access publication 5 August 2015
RHEUMATOLOGY
Original article
Periodontal pathogens participate in synovitis in
patients with rheumatoid arthritis in clinical
remission: a retrospective case–control study
Yuko Kimura1, Shuzo Yoshida1, Tohru Takeuchi1, Motoshi Kimura2,
Ayaka Yoshikawa1, Yuri Hiramatsu1, Takaaki Ishida1, Shigeki Makino1,
Yoshihiro Takasugi3 and Toshiaki Hanafusa1
Abstract
Objective. The objective of this study was to investigate the role of periodontal pathogens in RA in
remission.
Methods. Twenty-one patients with active RA and 70 patients in clinical remission, including 48 patients
with synovitis [US power Doppler (USPD)(+) group] and 22 patients without synovitis [USPD() group]
were clinically assessed by US. CRP, ESR, haemoglobin, MMP-3, RF and ACPA were measured. Antibody
titres against four types of periodontal pathogen [Aggregatibacter actinomycetemcomitans, Eikenella
corrodens (Ec), Porphyromonas gingivalis and Prevotella intermedia (Pi)] were analysed using ELISA.
Conclusion. More than half of RA patients in remission showed persistent synovitis. This synovitis may be
associated with periodontal disease-causing Pi. Thus, treating periodontal disease should also be considered in order to achieve more profound remission of RA.
Key words: rheumatoid arthritis, periodontitis, ultrasonography, power Doppler, clinical remission, periodontal
pathogen.
Rheumatology key messages
Musculoskeletal ultrasonography examination is useful for assessment of residual synovitis in RA in remission.
The persistence of synovitis may be associated with periodontal disease-causing Prevotella intermedia in RA
patients.
. Periodontal therapy should be considered to achieve more profound remission of RA.
.
.
1
Department of Internal Medicine (I), Osaka Medical College,
Department of Hygiene and Public Health, Division of Preventive and
Social Medicine, Osaka Medical College and 3Department of
Anesthesiology, Faculty of Medicine, Kinki University, Osaka, Japan
2
Submitted 5 November 2014; revised version accepted 26 June 2015
Correspondence to: Tohru Takeuchi, Department of Internal Medicine
(I), Osaka Medical College, Daigaku-Machi 2–7, Takatsuki, Osaka 5698686, Japan. E-mail: [email protected]
Introduction
RA is a systemic inflammatory disease characterized by
polyarthritis. Recently, it has become possible to suppress disease activity and to achieve clinical remission
in many RA patients with early intervention using synthetic
DMARDs such as MTX and biologic DMARDs [1–4].
! The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
CLINICAL
SCIENCE
Results. Musculoskeletal US examination showed that 68.6% of patients with RA in clinical remission
exhibited synovitis. CRP, ESR, haemoglobin, MMP-3 and RF levels in both the USPD(+) and USPD()
groups were clearly lower compared with the RA group in non-remission. The IgG serum antibody titre
against Ec in the non-remission RA(+) group was significantly greater than that in the USPD(+) group, and
the IgG antibody titre against Pi in the non-remission RA and USPD(+) groups was greater than in the
USPD() group.
Yuko Kimura et al.
However, both inflammation in the synovial tissues and
progressive destruction of joints have been observed on
musculoskeletal US in some RA patients in clinical remission [5–8]. It is unclear what factors contribute to the
residual synovitis detected on musculoskeletal US.
Environmental factors such as smoking, periodontal
pathogens and gut flora are known to be involved in the
onset of RA [9–12]. In particular, there are numerous studies reporting a strong association between RA and periodontal diseases [13–15]. Joint tissue destruction in RA
and periodontal tissue destruction in periodontal disease
have been shown to exhibit similar pathologies and have
therefore been suggested to have bidirectional causality
[16]. Porphyromonas gingivalis (Pg) is the only oral bacterium that produces the enzyme peptidylarginine
deiminase, and it has been suggested that it is involved
in the production of ACPA [17, 18]. Patients with active RA
have high serum IgG antibody titre against Pg [17, 18],
thus suggesting involvement in active RA. Thus, periodontal pathogens may also be involved in the pathology of RA
in clinical remission.
In this study, to investigate the role of periodontal
pathogens in RA in remission, we examined the association of synovitis (detected by musculoskeletal US and
serum IgG antibody titres) with periodontal pathogens
in patients with RA in remission. Furthermore, we also
investigated their association with established biomarkers
for RA.
Methods
We investigated 91 patients with RA who received treatment on an outpatient basis at the Department of Internal
Medicine (I), Osaka Medical College Hospital between
September 2012 and August 2013. All patients met the
ACR classification criteria for RA [19] and were evaluated
by DAS28-CRP [20]. Patients who underwent RA treatment for 53 months and subsequently maintained remission (DAS28-CRP < 2.3) for 56 months [21] were
considered to have RA in clinical remission. Those who
did not meet the DAS28-CRP–based remission criteria
were considered to be RA in non-remission patients [21].
Clinical assessment
Information on gender, age, duration of disease and treatment drugs for RA (MTX, biologic drugs, non-MTX synthetic DMARDs, CSs, antibiotics and NSAIDs)] were
obtained from medical charts and RA patients. Two
rheumatologists examined all patients and assessed
tender and swollen joints. The DAS 28-CRP and DAS28ESR [22, 23] were calculated for all RA patients.
Evaluation with HAQ [24–26] was conducted in RA
patients in clinical remission.
Ultrasonographic assessment
On the same day as physical examination, RA patients in
clinical remission underwent US assessment by two sonographers. Twenty-eight joints (bilateral knees, shoulders,
elbows, wrists, MCP joints 1–5 and proximal IP joints 1–5)
2258
were investigated by musculoskeletal US using both greyscale (GS) and power Doppler (USPD) modes of an US
diagnostic system (Viamo, Toshiba Medical Systems
Corporation, Tochigi, Japan). Synovitis was assessed in
the GS and USPD modes in accordance with the
Outcome Measures in Rheumatology US Taskforce
guidelines [27]. A semi-quantitative scoring scale (grade
0: absent; grade 1: mild; grade 2: moderate; grade 3:
marked) [28] was used for each parameter. Total GS
and USPD scores were calculated from the sum of
scores for 28 joints [29].
Laboratory determinations
Using blood samples collected from all RA patients, CRP
(reference value 40.25 mg/dl), ESR (0–14 mm/h), haemoglobin (Hb) (11.5–14.7 g/dl), MMP-3 (17.3–59.7 ng/ml), RF
(415 IU/l) and ACPA (<4.5 U/ml) were measured.
The antibody titres against four types of periodontal
pathogen [Aggregatibacter actinomycetemcomitans (Aa)
and Eikenella corrodens (Ec), which are facultative anaerobes; Pg and Prevotella intermedia (Pi), which are obligate
anaerobes] were measured using ELISA (Leisure Inc.,
Nagasaki, Japan), and are given as standardized values
for all RA patients. In accordance with the protocols
described by Sugi et al. [30], standardized values corrected for serum antibody titres of healthy subjects (age,
20–29 years) were calculated using the following equation.
Standardized value ¼
IgG titre of patient–mean IgG titre of healthy subjects
S:D: determined by mean IgG titre of healthy subjects 2
Assessment of periodontal disease
Number of teeth, mean probing pocket depths and clinical
attachment level were measured in all RA patients by a
highly trained dentist.
Statistical analyses
Categorical and quantitative variables were, respectively,
described as number (%) and median (25th, 75th percentile). Data were analysed using Prism software 5.0
(Graph-Pad, San Diego, CA, USA). For group comparisons between two groups, the two-tailed Mann–Whitney
test for skewed variables was used. For group comparisons between three or four groups, the Kruskal–Wallis test
followed by Dunn’s multiple comparison test for skewed
variables was performed. The Chi-squared test for independence was used to analyse contingency tables. A
value of P < 0.05 was considered to be statistically
significant.
All participants provided written informed consent prior
to enrolling in the study, according to the Declaration of
Helsinki (General Assembly October 2008), and this study
was conducted with the approval of the Medical Ethics
Committee of Osaka Medical College (Approval
number:1103).
www.rheumatology.oxfordjournals.org
Periodontal disease and RA
Results
The study included 21 patients with RA in non-remission
(non-remission RA group) and 70 patients with RA in remission. Patients with RA in remission were divided into
two groups depending on their total USPD score from
musculoskeletal US examination; patients with total
USPD score 51 were considered positive for synovitis
[USPD(+) group, 48 patients], and patients with a score
of 0 were considered negative for synovitis [USPD()
group, 22 patients]. One patient in the non-remission RA
group was complicated with SS, but no patient had SS in
the remission RA group.
Clinical assessment
Demographic data are shown in Table 1. There were no
differences in age, gender or duration of RA between any
of the groups. MTX was the most commonly used synthetic DMARD and was used for 62 RA patients (68%) in
this study. There were no differences in MTX dose or percentage undergoing biologic DMARD therapy between
the groups. Usage of synthetic DMARDs other than MTX
was 76% for the non-remission RA group, which was
greater than the 44% and 41% seen in the USPD(+) and
USPD() groups, respectively (P = 0.0269). Synthetic
DMARDs other than MTX in this study included salazosulphapyridine (21 patients, 23%), tacrolimus (17 patients,
19%) and bucillamine (12 patients, 13%), and the usage
frequencies of these medications did not differ between
the groups (P = 0.1094). The usage frequencies of prednisolone, antibiotics and NSAIDs were greater in the nonremission RA group when compared with the USPD(+)
and
USPD()
groups
(P < 0.0001,
P < 0.0001,
P = 0.0029). Prednisolone is a risk factor for opportunistic
infections, such as Pneumocystis jirovecii. To prevent infection with this pathogen, most patients received
sulphadiazine–trimethoprim
concomitantly
with
prednisolone.
Sulphadiazine–trimethoprim was given to 11 patients
with remission RA (12%) and 9 patients with nonremission RA (43%). Evaluation of physical function by
HAQ showed no differences between the USPD(+) and
USPD() groups (Table 2). Both groups showed diminished scores for DAS28-CRP and DAS28-ESR when compared with the non-remission RA group (P < 0.001).
Ultrasonographic assessment and laboratory
determinations
Data on US assessment and serological indices are shown
in Table 2. Synovitis assessment in GS mode showed that
the total USPD score was lower in the USPD() group
when compared with the USPD(+) group (P < 0.001).
CRP, ESR, Hb, MMP-3 and RF levels in both the
USPD(+) and USPD() groups were clearly lower when
compared with the non-remission RA group. CRP, ESR,
Hb and MMP-3 levels in both the USPD(+) and USPD()
groups were all within reference ranges. Median values of
ACPA decreased in the order: non-remission RA group,
USPD(+) group and USPD() group; however, all values
were greater than reference values, and there were no
differences between the three groups.
A comparison of IgG antibody titres against periodontal
pathogens between groups is shown in Fig. 1. There were
no differences in IgG antibody titre for Aa and Pg between
any of the groups (P = 0.5553, 0.2488). The IgG antibody
titre against Ec was lower in the USPD(+) group than in the
non-remission RA group; no differences were observed
between the other groups. The IgG antibody titre against
Pi in the USPD() group was clearly lower when compared with the non-remission RA and USPD(+) groups
(P = 0.0388, Mann–Whitney test).
Assessment of periodontal disease
There was no difference in number of teeth between the
non-remission RA group, USPD (+) group and USPD ()
group [Median (25th centile, 75th centile): 22.5 (20.25,
25.75), 24.5 (15.0, 28.0) and 26.0 (21.5, 28.0), respectively
TABLE 1 Demographic data from subjects with active RA or RA in clinical remission
RA in clinical remission
Characteristic
Age, median (IQR), years
Females, n (%)
Duration of RA, median (IQR), years
Medication use
MTX, n (%)
Biologic DMARDs, n (%)
Non-biologic DMARDs, n (%)
Steroids, n (%)
Antibiotics, n (%)
NSAIDs, n (%)
RA in non-remission
(n = 21)
USPD (+)
(n = 48)
USPD ()
(n = 22)
70 (64–75.5)
17 (81)
6 (2.75–14.5)
61 (48.5–69)
35 (73)
8 (4–15)
57 (54.5–69.5)
19 (86)
3 (1.75–8.5)
11
9
16
14
11
17
38
16
21
7
6
19
13
7
9
1
1
8
(52)
(43)
(76)
(67)
(52)
(81)
(79)
(33)
(44)
(15)
(13)
(40)
(59)
(32)
(41)
(5)
(5)
(36)
P-value
0.0831
0.4216
0.1399
0.0518
0.6964
0.0269
<0.0001
<0.0001
0.0029
P-value by Kruskal–Wallis test or Chi-squared test. IQR: interquartile range; USPD (+): positive synovitis by power Doppler
synovitis grade; USPD (): negative synovitis by power Doppler synovitis grade.
www.rheumatology.oxfordjournals.org
2259
Yuko Kimura et al.
TABLE 2 Clinical and serological data from subjects with active RA or RA in clinical remission
RA in clinical remission
Variable
RA in non-remission
HAQ
DAS28-CRP
DAS28-ESR
Total GS score
CRP, mg/l
ESR, mm/h
Hb, g/dl
MMP-3, ng/ml
RF, IU/ml
ACPA, U/ml
NT
3.42 (2.86–4.35)
4.77 (4.07–5.55)
NT
0.17 (0.40–2.80)
37 (21.25–52.25)
11.1 (10.4–12.75)
215.8 (106.4–364.0)
119 (44–699)
75.2 (10.2–113.5)
USPD (+)
0.00
1.45
2.00
9
0.07
10
13.1
53.5
17.5
32.6
(0.00–0.34)
(1.16–1.70)**
(1.51–2.59)**
(7–14.75)
(0.03–0.13)**
(5.5–13)**
(12.4–13.9)**
(33.0–81.6)**
(4–33)**
(5.8–163.0)
0.00
1.24
1.76
5
0.04
6
13.0
38.9
6
16.3
USPD ()
P-value
(0.00–0.22)
(1.05–1.76)**
(1.28–2.20)**
(2–7)****
(0.02–0.06)**,***
(4.75–15)**
(11.6–14.2)*
(27.3–52.8)**
(0–25.5)**
(3.6–43)
0.3223
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.0002
<0.0001
<0.0001
0.2323
All values are given as median (interquartile range), unless otherwise stated. P-value by Kruskal–Wallis test, *P < 0.01 vs active
RA, **P < 0.001 vs active RA, ***P < 0.05 vs USPD (+), ****P < 0.001 vs USPD (+) by Dunn’s multiple comparison test. USPD (+):
positive synovitis by power Doppler synovitis grade; USPD (): negative synovitis by power Doppler synovitis grade; GS:
lateral views in greyscale mode; Hb: haemoglobin; NT: not tested.
FIG. 1 Antibody titres against periodontal pathogens in active RA patients and patients in clinical remission
Aa (ATCC29523)
Ec (FDC1073)
4
IgG standardized value
2
1
0
2
1
0
(-)
)
D
(+
SP
U
clinical remission
Pi (ATCC25611)
Pg (FDC381)
4
IgG standardized value
200
150
100
50
0
**
**
3
2
1
0
(-)
SP
U
D
SP
D
(+
on
n-
U
re
m
SP
is
D
si
(-)
(+
)
SP
D
U
n-
re
m
is
si
on
clinical remission
)
-1
-50
no
IgG standardized value
D
U
nno
no
clinical remission
no
SP
is
m
re
U
U
SP
SP
si
D
on
)
(+
D
si
is
m
re
n-
(-)
-1
on
-1
*
3
U
IgG standardized value
3
clinical remission
Based on the findings of power Doppler by US, patients in clinical remission were divided into two groups: USPD(+) and
USPD(). Periodontal pathogens tested in this study were Aggregatibacter actinomycetemcomitans (Aa), Eikenella
corrodens (Ec), Porphyromonas gingivalis (Pg) and Prevotella intermedia (Pi).
2260
www.rheumatology.oxfordjournals.org
Periodontal disease and RA
(P = 0.51)]. Mean probing pocket depth and clinical attachment levels, which are measures of the progression and
severity of periodontitis, did not differ between the groups
[probing pocket depth: 2.38 (2.08, 2.62), 2.66 (2.31, 3.03)
and 2.58 (2.24, 3.26), respectively (P = 0.23); clinical attachment level: 4 (1.5, 5), 4 (1, 5) and 3 (1.5,5), respectively
(P = 0.73)]. One patient in the non-remission RA group and
five patients in the USPD(+) group had 45 teeth remaining.
Discussion
We assessed synovitis by musculoskeletal US and
measured serum IgG antibody titre against periodontal
pathogens in RA patients in clinical remission and nonremission. Musculoskeletal US examination showed that
68.6% of patients with RA in clinical remission had grade
51 blood-flow pattern and exhibited synovitis. In
addition, the serum IgG antibody titre against Ec in the
non-remission RA(+) group was significantly greater
when compared with the USPD(+) and USPD() groups,
and the IgG antibody titre against Pi in the non-remission
RA and USPD(+) groups was greater than that of the
USPD() group. These findings suggest that RA is
associated with infection by periodontal pathogens.
Musculoskeletal US examination is useful for the diagnosis of RA and evaluation of its activity. It has been reported that synovitis is detected by musculoskeletal US in
half of RA patients who have achieved clinical remission
[5–8], and our results are consistent with these reports.
Moreover, similar to the report by Brown et al. [31],
patients with active RA and in clinical remission can be
distinguished by serological biomarkers and disease
activity scores such as DAS28; however, it has been suggested that the presence of synovitis cannot be predicted.
It has been reported that progression of joint destruction
may occur when a blood flow of grade 52 is observed in
the synovium by US [31–34]. Therefore, in RA patients in
clinical remission, assessment by musculoskeletal US
examination is important, in addition to established biomarkers and disease activity indices.
RA patients have a high incidence of periodontal disease, and periodontal disease can be readily aggravated.
It has been reported that RA patients with periodontal
disease have high arthritis activity [35], and IgG antibody
titres against periodontal pathogens have been investigated as new biomarkers for RA. Numerous anaerobic
periodontal pathogens have been identified in the periodontal pockets of patients with periodontal disease,
and the presence of Aa, Ec, Pg and Pi is implicated in
the progression and severity of periodontal disease
[36–38]. Pg is considered to be involved in the production
of ACPA, which is related to the aetiology and joint
destruction of RA [39, 40]. There have been very few
reports in which RA has been associated with Pi and Ec.
In the present study, we demonstrated that IgG antibody
titres against Pi and Ec were associated with the
disease activity of RA, and that these might be new biomarkers for RA.
Pi activates macrophages and induces production of
IL-6 and TNF-a [41]. These inflammatory cytokines are
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known to play a role in periodontal destruction in periodontitis [41–43] and have been also reported to be
involved in synovitis, as well as in the joint destruction in
RA. Serum antibody levels against Pi were significantly
higher in RA patients than in the healthy controls [44].
Significantly higher levels of IgG antibodies against Pi
were demonstrated in SF from RA patients than in SF
from OA patients [45]. Martinez-Martinez et al. [43] and
Moen et al. [46] reported that bacterial DNA of Pi was
frequently detected in the SF of patients with RA. The
present study demonstrated that IgG antibody titre
against Pi in the non-remission RA group and the USPD
(+) group was greater than that of the USPD () group.
Thus, it is suggested that Pi is closely related to synovitis
in RA, but the causal relationship remains unclear.
Furthermore, it is necessary to determine whether the
high antibody titre decreases with treatment for RA, or
whether treatment for periodontitis could affect the disease activity of RA.
There are opposing opinions regarding the association
between Ec or Pg and RA. Okada et al. [47] reported
that the antibody titre of Ec in RA patients is lower
than that of healthy subjects. In contrast, Ziebolz et al.
[48] showed that Fusobacterium nucleatum (98%),
Peptostreptococcus micros (88%) and Ec (91%) were frequently present in the periodontal tissues of RA patients
with periodontal disease. However, Pg (58%) was
reported to be present at a lower frequency. In this
study, the IgG antibody titre against Ec was elevated
only in non-remission RA patients. The serum IgG antibody titre against Pg is reported to be elevated in RA patients and to subsequently decrease with treatment [47].
Martinez-Martinez et al. [43] reported that bacterial DNA
was frequently detected in the serum and SF of RA
patients. However, the present study did not reveal any
differences in IgG antibody titre against Pg between
any of the groups. These discrepancies indicate that
multiple periodontal pathogens are involved in the
pathology of RA. In addition, antibiotics such as
sulphadiazine–trimethoprim, or DMARDs such as salazosulphapyridine may also be related to antibody titres
against periodontal pathogens [49].
It has been reported that periodontal disease in RA
patients can easily become aggravated [35]. In the present study, periodontal disease assessments revealed no
differences between the extent of periodontal tissue
destruction and RA disease activity. Similar serum antibody titres for each of four periodontal pathogens were
observed in patients with fewer remaining teeth and patients with greater numbers of remaining teeth (data not
shown). It has recently been suggested that periodontal
pathogens are able to migrate to other tissues, such as
the coronary artery and liver via circulation or the digestive
tract [50, 51]. Migration to sites other than periodontal
tissues may affect serum antibody titres of periodontal
pathogens, and further investigation is necessary to confirm these possibilities.
The limitations of this study were as follows: first, as
patients with active RA were already receiving treatment
2261
Yuko Kimura et al.
with medications such as DMARDs, antibiotics and steroids, it is possible that drug treatment affected the serum
antibody titres of periodontal pathogens; and second, the
results in this study did not include data obtained through
repeated measurements in the same subjects at each of
the different disease stages. To understand the effects of
periodontal pathogens on disease stage, it will be necessary to evaluate long-term treatment effects for each
patient and the association with antibody titres. We
could be commercially available to investigate only IgG
antibodies to periodontal pathogens, but not other
classes of antibody. Further studies are needed to evaluate IgA and IgM antibodies.
Acknowledgements
Y.K., S.Y. and T.T. designed the study; T.I. and A.Y. assessed the physical examination of joints; Y.K. and S.Y.
conducted the US examination; M.K. assessed the periodontal disease; Y.K., M.K. and S.M. collected and analysed the data; Y.K., M.K., T.T. and Y.T. wrote the
manuscript. Y.K., M.K., T.T. and T.H. revised the
manuscript.
Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript.
Disclosure statement: The authors have declared no
conflicts of interest.
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