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Journal of Oral Science, Vol. 59, No. 1, 55-62, 2017

Original

Stimulated salivary flow rate and oral health status


Yoshihiro Shimazaki1,2), Bohan Fu1), Koji Yonemoto3,4), Sumio Akifusa1,5),
Yukie Shibata1), Toru Takeshita1), Toshiharu Ninomiya6), Yutaka Kiyohara3),
and Yoshihisa Yamashita1)
1)Section of Preventive and Public Health Dentistry, Division of Oral Health, Growth and Development,
Faculty of Dental Science, Kyushu University, Fukuoka, Japan
2)Department of Preventive Dentistry and Dental Public Health, School of Dentistry,

Aichi Gakuin University, Nagoya, Japan


3)Department of Environmental Medicine, Graduate School of Medical Sciences,

Kyushu University, Fukuoka, Japan


4)Biostatistics Center, Kurume University, Kurume, Japan
5)Department of Health Management, School of Oral Health Sciences, Kyushu Dental University,

Kitakyushu, Japan
6)Division of Research Management, Center for Cohort Studies, Graduate School of Medical Sciences,

Kyushu University, Fukuoka, Japan


(Received May 10, 2016; Accepted July 4, 2016)

Abstract: This study examined the relationship ratio for broad periodontal disease, than did those
between stimulated salivary flow rate and oral with a flow rate >3.5 mL/min. In spline models, the
health status in an adult population. Multinomial odds ratio for teeth with dental caries or periodontal
multivariate logistic regression analysis was used to disease increased with reduced saliva secretion. The
examine the associations of salivary flow rate with present findings suggest that decreased saliva secre-
dental caries status and periodontal status at the tion affects both dental caries and general periodontal
individual level among 2,110 Japanese adults with health status.
10 teeth. Then, a spline model was used to examine
the nonlinear relationship between salivary flow rate Keywords: stimulated salivary flow; dental caries;
and teeth with dental caries or periodontal disease in periodontal disease; multilevel analysis;
multilevel analysis. Odds ratios were calculated for a spline model.
1.0-mL/min reduction in salivary flow rate at a point.
After adjusting for confounding variables, partici-
pants with a flow rate 3.5 mL/min had significantly Introduction
higher odds ratios for high caries status, and partici- Saliva is important in oral functions such as mastication
pants with a flow rate 1.4 mL/min had a higher odds and swallowing, the buffering function of pH, antimicro-
bial activity, and cleaning action (1-3). Thus, a decrease
Correspondence to Dr. Yoshihisa Yamashita, Section of Preventive in the ability to salivate likely affects various oral
and Public Health Dentistry, Division of Oral Health, Growth and health-related issues. However, information on the actual
Development, Faculty of Dental Science, Kyushu University, conditions associated with saliva production in adults is
3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Fax: +92-642-6354 E-mail: yoshi@dent.kyushu-u.ac.jp
limited (4-6). Thus, we examined salivary flow rate in an
adult population.
J-STAGE Advance Publication: December 28, 2016
Color figures can be viewed in the online issue at J-STAGE. Many previous studies reported a relationship between
doi.org/10.2334/josnusd.16-0372 the amount of saliva secretion and oral diseases such
DN/JST.JSTAGE/josnusd/16-0372 as dental caries and periodontal disease. In particular, a
56

decline in saliva secretion increased the risk of dental caries retained teeth except for third molars, because partially
(7-10). However, the extent to which caries risk increases impacted third molars frequently have pseudopockets.
because of decreased saliva production is unclear. A few Examination reliability for the periodontal assessment
studies have suggested that decreased saliva secretion was verified by interexaminer calibration of volunteers
affects periodontal disease (8,9,11), although others have with characteristics similar to those of the study popula-
questioned whether such an association exists (4,12,13). tion. The Cohen value exceeded 0.8, indicating very
One study reported that few subjects with lower saliva good interexaminer agreement. Oral hygiene was evalu-
secretion had deep periodontal pockets (14). Thus, there ated using the plaque index, and the mean plaque index
is no consensus regarding the association between saliva score for each subject was included in the analysis.
secretion and periodontal disease. Stimulated saliva was sampled between 8:00 and
This study collected information on the distribution of 10:30 AM, during a morning fast. During sampling,
stimulated salivary flow rates in a community-dwelling participants were asked to sit in a chair. Saliva was stimu-
adult population and analyzed the association of reduced lated by chewing fruit-flavored gum for 2 min and then
stimulated salivary flow rate with oral health status, collected from each participant. Participants expectorated
including dental caries and periodontal disease. the accumulated saliva into a sterile tube. After 2 min, the
amount of collected saliva was measured by deducting
Materials and Methods the weight of the tube from the total weight including the
Study population tube, and salivary flow rate was expressed in mL/min,
The study participants were recruited in 2007 in the town with the specific gravity of saliva defined as 1.0.
of Hisayama, a suburb of the Fukuoka metropolitan
area, in southern Japan. The town registry listed 3,810 General examination and questionnaire
residents aged 40-79 years, 2,861 (75.1%) of whom A blood sample was collected from the antecubital vein
provided written informed consent to participate in the in the morning after an overnight fast, and fasting plasma
study and underwent a comprehensive examination. glucose values were categorized into three groups (119,
Dental and medical examinations were performed on 120-125, 126 mg/dL). Body mass index was calculated
2,669 dentate and edentulous adults. All participants as the weight in kilograms divided by the square of the
with at least 10 teeth were included in the analysis; 559 height in meters.
participants who had fewer than 10 teeth or were unable Each subject completed a self-administered question-
to provide sufficient data were excluded because of the naire in advance that included smoking habit (never,
inherent difficulties of assessing periodontal health in former, current) and toothbrushing frequency. A former
these individuals. As study of individuals with fewer smoker was defined as a subject who had quit smoking
teeth indicated that they were more susceptible to poor more than 1 year before the day of the examination.
periodontal conditions (15). The final study sample Toothbrushing frequency was divided into three catego-
comprised 2,110 participants (931 men, 1,179 women). ries (1, 2, 3 times/day).
Written informed consent was obtained from all
participants, in accordance with the World Medical Asso- Statistical analysis
ciation Declaration of Helsinki. The Ethics Committee A previous study showed that an appropriate cut-off value
of the Kyushu University Faculty of Dental Sciences, for stimulated salivary flow rate was 1.4 mL/min when
Fukuoka Japan, approved the study design, data collec- using plum-flavored gum to diagnose Sjgren syndrome
tion methods, and procedure for obtaining informed (17). Therefore, in view of its distribution, salivary flow
consent (approval 20B-1). rate was divided into four categories (expressed as mL/
min): 1.40, n = 282 (13.3%); 1.41-2.50, n = 554 (26.3%);
Oral examination and saliva collection 2.51-3.50, n = 621 (29.4%); and 3.51, n = 653 (30.9%).
Each subject received an oral health examination in a Two cut-off points for periodontal status were used to
supine position under adequate artificial light in a normal divide the participants into three categories. Participants
or portable dental chair. Using the methods of the Third without deep periodontal pockets were classified as
National Health and Nutrition Examination Survey (16), having good periodontal status and those at approxi-
one of nine dentists performed a periodontal examination mately the 15th percentile were classified as having poor
with standardized probing technique. A periodontal probe periodontal status, according to the percentage of teeth
was used to examine pocket depth and clinical attach- with both a pocket depth and clinical attachment loss 4
ment loss on the mesiobuccal and mid-buccal sites of all mm, as follows: 0%, n = 1,033 (49.0%); 0.1-19.9%, n =
57

125

100
Number of subjects
75

50

25

0
0 2 4 6 8 10
Stimulated salivary ow rate (mL/min)
Fig. 1Distribution of stimulated salivary flow rates.

739 (35.0%); and 20%, n = 338 (16.0%). The percentage of dental health investigation. These variables were
of dental caries (decayed or filled teeth) was divided into age, sex, smoking habit (0: never, 1: former, 2: current),
three categories using two cut-off points, similar to the body mass index (kg/m2), fasting plasma glucose (mg/
percentages used for periodontal status, namely <70%, dL) (0: 109, 1: 110-125, 2: 126), mean plaque index,
n = 1,258 (59.6%); 70-89.9%, n = 571 (27.1%); and frequency of toothbrushing (times/day) (0: 1, 1: 2, 2:
90%, n = 281 (13.3%). Multinomial logistic regression 3), number of teeth, location of tooth (0: lower incisor
analyses were used to calculate odds ratios (ORs) and or canine, 1: upper incisor or canine, 2: lower premolar,
95% confidence intervals (CIs) for the effects of sali- 3: upper premolar, 4: lower molar, 5: upper molar), and
vary flow rate and other variables on dental caries and amount of stimulated saliva (mL/min). P values < 0.05
periodontal status. Age, sex, smoking habit, body mass were considered to indicate statistical significance. SPSS
index, toothbrushing frequency, number of teeth, mean ver.19.0 for Macintosh (IBM SPSS Japan, Tokyo, Japan)
plaque index, and fasting plasma glucose level were was used for the data analysis.
included as confounding variables in the multivariate
multinomial logistic regression analysis. Additionally, Results
using a spline model with a model selection method Figure 1 shows the distribution of stimulated salivary
proposed by Kawaguchi et al., we examined the possi- flow rate in a community-dwelling adult population (age
bility of a nonlinear association of salivary flow rate with 40-79 years). The mean (standard error, standard devia-
teeth with dental caries and teeth with periodontal disease tion) amount of stimulated saliva was 2.94 (0.0293, 1.38)
(18). Stratified descriptive information was calculated mL/min; 282 (13.3%) participants had a flow rate of 1.4
using the subject and teeth as units of analysis. Dental mL/min.
caries (tooth decayed or filled) and periodontal disease Table 1 shows the associations of salivary flow rate
(teeth with both a pocket depth and clinical attachment and other variables with dental caries. Salivary flow
loss 4 mm) were defined as the main outcome variables. rate, sex, fasting plasma glucose, age, number of teeth,
A generalized estimating equation logistic regression and mean plaque index were significantly associated
model considering tooth factors (first level) nested within with dental caries. As compared with participants with
subject factors (second level) was used to explain varia- a rate of 3.51 mL/min, those with a salivary flow rate
tion in binary dependent variables. ORs and 95% CIs of 1.41-3.50 mL/min had a significantly higher OR for
for teeth with dental caries or periodontal disease were dental caries in 70% to 89.9% of their teeth. Moreover,
calculated for a 1.0-mL/min reduction in salivary flow participants with a rate of 2.5 mL/min had a significantly
rate at a point. In the analysis, the basic level, tooth, higher OR for having dental caries in 90% of their teeth
was nested in the upper level, subject. Ten factors were (Table 1). Table 2 shows the associations of salivary flow
considered as possible risk factors (covariates) for dental rate and other variables with periodontal status. Salivary
caries (decayed or filled teeth) and periodontal disease flow rate, sex, smoking habit, age, number of teeth, mean
and were always included in the model for the purpose plaque index, and body mass index were significantly
58

Table 1 Associations of salivary flow rate and other variables with dental caries
DF teeth (%) Dependent variable: DF teeth (%)
<70 70-89.9 90 70-89.9 vs. <70 90 vs. <70
Independent variable (n = 1,258) (n = 571) (n = 281) Adjusted OR (95% CI) Adjusted OR (95% CI)
n (%)
Stimulated salivary flow rate
3.51 mL/min 455 (36.2) 139 (24.3) 59 (21.0) 1 1
2.51-3.50 mL/min 357 (28.4) 193 (33.8) 71 (25.3) 1.53 (1.16-2.00)** 1.21 (0.78-1.86)
1.41-2.50 mL/min 296 (23.5) 169 (29.6) 89 (31.7) 1.46 (1.10-1.94)** 1.80 (1.18-2.75)**
1.40 mL/min 150 (11.9) 70 (12.3) 62 (22.1) 1.12 (0.78-1.61) 1.79 (1.11-2.90)*
Sex
Male 627 (49.8) 202 (35.4) 102 (36.3) 1 1
Female 631 (50.2) 369 (64.6) 179 (63.7) 1.82 (1.35-2.45)*** 1.72 (1.09-2.70)*
Smoking habit
Never smoker 671 (53.3) 357 (62.5) 182 (64.8) 1 1
Former smoker 283 (22.5) 129 (22.6) 50 (17.8) 1.28 (0.93-1.76) 0.79 (0.48-1.31)
Current smoker 304 (24.2) 85 (14.9) 49 (17.4) 0.83 (0.59-1.17) 1.02 (0.62-1.69)
Toothbrushing frequency
3 times/day 208 (16.5) 92 (16.1) 50 (17.8) 1 1
2 times/day 649 (51.6) 316 (55.3) 137 (48.8) 1.21 (0.90-1.62) 1.04 (0.68-1.59)
1 times/day 401 (31.9) 163 (28.5) 94 (33.5) 1.13 (0.81-1.58) 1.00 (0.62-1.60)
Fasting plasma glucose
119 mg/dL 961 (76.4) 444 (77.8) 219 (77.9) 1 1
120-125 mg/dL 179 (14.2) 81 (14.2) 32 (11.4) 0.93 (0.68-1.27) 0.54 (0.34-0.87)*
126 mg/dL 118 (9.4) 46 (8.1) 30 (10.7) 0.75 (0.51-1.10) 0.69 (0.41-1.16)
Mean (SD)
Age (years) 57.1 (9.4) 60.6 (10.1) 66.0 (9.1) 1.02 (1.01-1.03)*** 1.06 (1.04-1.08)***
Number of teeth present 25.8 (4.0) 23.9 (4.1) 19.4 (5.5) 0.91 (0.89-0.94)*** 0.80 (0.77-0.82)***
Mean plaque index 0.6 (0.6) 0.7 (0.6) 1.0 (0.7) 1.21 (1.01-1.46)* 1.85 (1.44-2.38)***
BMI (kg/m2) 23.4 (3.4) 23.1 (3.5) 23.1 (3.4) 0.98 (0.95-1.01) 0.97 (0.92-1.01)
n = 2,110. DF: decayed or filled, OR: odds ratio, CI: confidence interval, BMI: body mass index, SD: standard deviation, *: P < 0.05, **: P < 0.01,
***: P < 0.001.

associated with periodontal status. Participants with a not associated with the risk of a tooth having periodontal
flow rate 1.40 mL/min had a significantly higher OR for disease, but the OR increased and was significant when
having 20% teeth with periodontal disease, as compared salivary flow rate was less than approximately 2.7 mL/
with participants with a flow rate of 3.51 mL/min (Table min.
2).
Next, we evaluated the nonlinear effect of salivary flow Discussion
rate on teeth with dental caries or teeth with periodontal Because information on hyposalivation in the general
disease using the ORs from the spline model. For illus- adult population is limited, this study examined the
tration, we focused on the variable salivary flow rate distribution of stimulated salivary flow in Japanese adults
because of its nonlinear effect. Figure 2 shows the ORs participating in a community-based health examination.
for decayed or filled teeth, and Fig. 3 shows the ORs for A gum test is often used to evaluate oral dryness, and
teeth with a pocket depth and clinical attachment loss 4 a value of 1.0 mL/min has been used as a cutoff value
mm, for a 1.0-mL/min reduction in salivary flow rate, as for stimulated salivary flow in the diagnosis of Sjgren
computed from the spline model, assuming all other vari- syndrome (19). If flavored gum is used, a salivary flow
ables remained constant. Figure 2 shows that, down to 2.15 cut-off value of 1.4 mL/min is recommended for iden-
mL/min, caries risk for an individual tooth continued to tification of hyposalivation. According to that criterion,
increase gradually as salivary flow decreased, but the OR about 13.3% of adults 40 years or older have a stimulated
became nonsignificant when salivary flow rate was less salivary flow equal to or lower than that value. Using a
than approximately 2.15 mL/min. A rate less than about modification of the Saxon test, a previous study (6) of
2.15 mL/min did not further increase the risk of dental a community-dwelling Japanese population aged 20-90
caries, although the risk of dental caries remained high. years reported that about 14% of participants had low
Figure 3 shows that a salivary flow rate >2.7 mL/min was stimulated salivary flow (2.04 g/2 min); this proportion
59

Table 2 Associations of salivary flow rate and other variables with periodontal status
PD and CAL 4 mm (%) Dependent variable: PD and CAL 4 mm (%)
0 0.1-19.9 20 0.1-19.9 vs. 0 20 vs. 0
Independent variable (n = 1,033) (n = 739) (n = 338) Adjusted OR (95% CI) Adjusted OR (95% CI)
n (%)
Stimulated salivary flow rate
3.51 mL/min 323 (31.3) 229 (31.0) 101 (29.9) 1 1
2.51-3.50 mL/min 326 (31.6) 203 (27.5) 92 (27.2) 0.93 (0.71-1.21) 1.04 (0.72-1.50)
1.41-2.50 mL/min 263 (25.5) 213 (28.8) 78 (23.1) 1.18 (0.90-1.55) 1.18 (0.80-1.73)
1.40 mL/min 121 (11.7) 94 (12.7) 67 (19.8) 1.14 (0.80-1.61) 1.98 (1.23-3.06)**
Sex
Male 371 (35.9) 356 (48.2) 204 (60.4) 1 1
Female 662 (64.1) 383 (51.8) 134 (39.6) 1.00 (0.75-1.33) 0.64 (0.43-0.93)*
Smoking habit
Never smoker 685 (66.3) 384 (52.0) 141 (41.7) 1 1
Former smoker 211 (20.4) 179 (24.2) 72 (21.3) 1.33 (0.97-1.81) 1.11 (0.72-1.71)
Current smoker 137 (13.3) 176 (23.8) 125 (37.0) 2.67 (1.93-3.70)*** 4.14 (2.73-6.29)***
Toothbrushing frequency
3 times/day 194 (18.8) 103 (13.9) 53 (15.7) 1 1
2 times/day 577 (55.9) 370 (50.1) 155 (45.9) 1.08 (0.81-1.44) 0.85 (0.58-1.26)
1 times/day 130 (25.4) 266 (36.0) 130 (38.5) 1.26 (0.91-1.73) 0.83 (0.54-1.28)
Fasting plasma glucose
119 mg/dL 854 (82.7) 533 (72.1) 237 (70.1) 1 1
120-125 mg/dL 111 (10.7) 126 (17.1) 55 (16.3) 1.30 (0.97-1.75) 1.20 (0.81-1.79)
126 mg/dL 68 (6.6) 80 (10.8) 46 (13.6) 1.32 (0.92-1.91) 1.57 (0.99-2.48)
Mean (SD)
Age (years) 57.3 (9.9) 61.4 (10.0) 60.6 (9.5) 1.04 (1.03-1.05)*** 1.01 (1.00-1.03)
Number of teeth present 25.5 (4.2) 24.1 (4.6) 21.9 (5.4) 0.97 (0.94-0.99)** 0.89 (0.86-0.92)***
Mean plaque index 0.5 (0.5) 0.7 (0.6) 1.0 (0.7) 1.86 (1.53-2.25)*** 3.29 (2.60-4.16)***
BMI (kg/m2) 22.9 (3.4) 23.6 (3.6) 23.6 (3.2) 1.04 (1.01-1.08)** 1.04 (1.00-1.09)
n = 2,110. PD: pocket depth, CAL: clinical attachment loss, OR: odds ratio, CI: confidence interval, BMI: body mass index, SD: standard deviation,
*: P < 0.05, **: P < 0.01, ***: P < 0.001.

2.0

1.5
Odds ratio

1.0

0.5

0.0
1 2 3 4 5
Stimulated salivary ow rate (mL/min)
Fig. 2Odds ratio for a tooth being decayed or filled for a 1.0-mL/min reduction in salivary flow rate at
a point. Odds ratios were adjusted for age, sex, smoking habit, body mass index, fasting plasma glucose,
mean plaque index, frequency of toothbrushing, number of teeth present, and location of teeth. The solid
line shows the odds ratio based on a spline model and the shaded band shows the 95% confidence interval.

was close to that in the present study. In Sweden, the aged 65 years had a stimulated salivary flow rate of 1.0
prevalence of a low (<1.0 mL/min) stimulated salivary mL/min or less (20). Salivary flow rate may be affected
flow rate was about 9% among dental patients aged 40 by differences in population characteristics and ethnicity.
years or older (5). In the United States, 35% of adults Although the present participants were residents of a
60

1.8

1.6

Odds ratio 1.4

1.2

1.0

0.8

1 2 3 4 5
Stimulated salivary ow rate (mL/min)
Fig. 3Odds ratio for a tooth having a pocket depth and clinical attachment loss 4 mm for a 1.0-mL/min reduction
in salivary flow rate at a point. Odds ratios were adjusted for age, sex, smoking habit, body mass index, fasting
plasma glucose, mean plaque index, frequency of toothbrushing, number of teeth present, and location of teeth. The
solid line shows the odds ratio based on a spline model and the shaded band shows the 95% confidence interval.

single town in Japan, the participation rate was high. cillus acidophilus in saliva and supragingival plaque were
Thus, our data are relevant to the distribution of stimu- significantly higher in patients with Sjgren syndrome
lated salivary flow in the Japanese adult population. than in control subjects and suggested that changes in
Decreased saliva secretion increases the risk of dental the microbial composition may affect individual risk
caries (7-10). Our study suggests that saliva volume of dental caries (24). Future microbial studies should
is inversely associated with the risk of dental caries. attempt to clarify the mechanism underlying the relation
Although the study participants were aged 40 years and between salivary flow rate and dental caries.
many had missing teeth, we were unable to identify the Although several studies have examined the relation
cause of tooth loss. We then defined dental caries status between salivary flow and periodontal disease, a few
as the proportion of decayed or filled teeth among teeth reports have suggested that individuals with lower sali-
present in participants having 10 teeth. Multivariate vary flow rates have higher risks for periodontal disease
analysis adjusted for number of present teeth and other (8,9,11). The present participants with a salivary flow rate
variables showed that lower stimulated salivary flow was 1.4 mL/min had a higher risk for extensive periodontal
significantly associated with a higher rate of dental caries. disease. The spline model for analysis at the tooth level
Although dental caries risk was not significantly higher showed that the inflection point for the risk of teeth with
(70% to 89.9% vs. <70% DF teeth) in participants with periodontal disease due to a 1.0-mL/min decrease in
the lowest saliva secretion (1.4 mL/min), we hypothe- saliva secretion was about 2.7 mL/min. A decrease of
size that this risk explains why many of these participants 1.0 mL/min from this value (i.e., 1.7 mL/min) was close
were in the highest dental caries category (90% DF to the high-risk value (about 1.4 mL/min) for extensive
teeth). In the multilevel spline model, caries risk for each periodontal disease in the present subject-level analysis.
tooth increased with reduced saliva secretion; however, These findings suggest that periodontal conditions are
when salivary flow was less than approximately 1.15 unchanged in persons with average stimulated salivary
mL/min (2.15-1.0 mL/min), the OR for dental caries did flow. Although low salivary flow increased the risk of
not further increase. dental caries over a wide range of salivary flow rates,
Both subject-level and multilevel analyses suggested the risk of periodontal disease due to low salivary secre-
that high salivary flow prevents dental caries and that a tion was higher only in the lower range of salivary flow.
decrease in saliva production might have a cariogenic Therefore, adverse periodontal effects may only occur at
effect. Sjgren syndrome is a systemic autoimmune a stimulated salivary flow rate below approximately 1.4
disease associated with hyposalivation (21), and patients mL/min for flavored gum chewing, which corresponds to
with this disease have many teeth with dental caries a rate of 1.0 mL/min for paraffin gum chewing-stimulated
(22,23). A previous study showed that levels of Lactoba- salivary flow. One study showed that low stimulated
61

salivary flow rate was associated with decreased risk of is less common, except in patients who specifically
having teeth with a pocket depth 4 mm among dentate complain of oral dryness. This study showed that low
subjects aged 75 years (14). This result appears to salivary flow rate may affect both dental caries and
contradict the findings of the present study; however, the general periodontal health. Thus, assessment of salivary
subjects of that study were older and more likely to be secretion in health examinations and at dental clinics
female, especially in groups with low salivary flow rates, may have an important role in evaluating patients future
and these factors may affect the difference in the relation risk of oral disease.
between salivary secretion and periodontal disease.
Studies have reported that periodontal status is poor Acknowledgments
in patients with Sjgren syndrome (22,23,25,26). In This work was supported by a Grant-in-Aid for Scientific Research
addition, plaque index scores were higher for Sjgren (No. 23390483, 25293428, and 25893177) from the Ministry of
syndrome patients than for control subjects (22,25), and Education, Culture, Sports, Science and Technology, Japan and by
stimulated salivary flow was inversely associated with the departmental budget of Kyushu University, Fukuoka, Japan.
plaque index score in Sjgren syndrome patients (26).
Conflict of interest
Serum antibody levels to periodontopathogens were
The authors declare that they have no competing interests.
significantly higher in Sjgren syndrome patients than
in control subjects (25). A case-control study suggested References
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