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doi: 10.46497/ArchRheumatol.2025.11039
Arch Rheumatol 2025;40(1):15-27
ORIGINAL ARTICLE
Association between frailty and oral function in rheumatoid arthritis
patients: A multi-center, observational study
Yasumori Sobue1, Mochihito Suzuki2, Yoshifumi Ohashi3, Ryo Sato2, Yusuke Ohno2, Junya Hasegawa2,
Takaya Sugiura2, Kenya Terabe2, Shuji Asai2, Shiro Imagama2
Frailty is a condition characterized by the
transitional phase between good health and
disability, involving age-related declines in
physical, cognitive, social, and oral abilities.1
Frailty can lead to serious health issues, even
with minor stressors, resulting in long-term
dependency on medical care and the need for
caregiving.2 In an increasingly aging society,
this increases healthcare costs and places a
burden on the caregiving system.3 Therefore,
early detection and management of frailty
are critical and would contribute to reducing
medical expenses, improving the quality
of life for older adults, and alleviating the
burden on caregiving resources. During the
novel coronavirus disease 2019 (COVID-19)
pandemic, the effect of frailty was significant,
with frail patients having a significantly higher
risk of in-hospital mortality, underscoring the
importance of frailty assessment in clinical
decision-making.4 The restrictions on going out
during the pandemic led to reduced physical
activity, which further accelerated the decline
in physical function among frail individuals and
exacerbated their vulnerability to adverse health
outcomes.5 Furthermore, limitations on social
interactions and opportunities to use one’s
voice likely contributed to declines in cognitive,
social, and oral abilities, deepening the overall
impact on the well-being of frail individuals.
ABSTRACT
Objectives: This study aims to investigate the association between frailty and oral func tion in
rheumatoid ar thritis (RA) patients and to identify practical markers for early frailt y detection and
potential intervention strategies.
Patients and methods: A multi-center observational cohort study (T-FLAG) included a total of
661 RA patients (475 males, 186 females; mean age: 68.5±13.5 years; range, 18 to 100 years) between
June 2023 and August 2023. Frailty was assessed using the Kihon Checklist (KCL) (frailty: score
≥8). Oral function scores were based on Question 13 (“difficult y eating hard foods”), Question 14
(“choking”), and Question 15 (“dry mouth”) of the KCL. Re ceiver operating charac teristic (ROC) curves
were generated to assess the association bet ween frailty and oral function scores. Multivariate
logistic regression was used to analyze factors associated with oral function.
Results: Among the 661 participants, 39.5% were frail. Frailt y rates tended to increase with
increasing oral function scores. The optimal cut-off score for oral function corresponding to
frailty was 2 points, with a specificity of 89.2% and a sensitivity of 54.8%. Multivariate analysis
identified age and Health Assessment Questionnaire-Disability Index (HAQ- DI) as signif icant
factors associated with oral function decline (i.e., a total score of ≥2 for Questions 13-15 of the KCL).
Conclusion: Frailty is strongly associated with oral func tion decline in RA patients. This finding
highlights the importance of monitoring the oral function of RA patients, since it not only reflects
physical function, but also serves as a potential marker of frailty. Targeted interventions to improve
oral function may play a vital role in reducing frailty risk and enhancing the overall well-being of RA
patients.
Keywords: Frailty; laughter; oral function; rheumatoid arthritis, the Kihon checklist.
Correspondence: Mochihito Suzuki, MD.
E-mail: mochihito0511@yahoo.co.jp
Received: December 01, 2024
Accepted: January 16, 2025
Published online: March 17, 2025
Citation: Sobue Y, Su zuki M, O hashi Y, Sat o R,
Ohno Y, Hase gawa J, et al . Associati on bet ween
frailt y and oral func tion in r heuma toid ar thritis
patie nts: A mu lti-c enter, ob serv ationa l stud y.
Arch Rhe umato l 2025;4 0(1):15-27. doi: 10.4 6497/
ArchRheumatol.2025.11039.
This is an o pen acc ess art icle under the te rms of
the Creative Commons At tribution-NonCommercial
Licens e, whic h permi ts use, d istr ibut ion and
reprod uct ion in any me dium, p rovide d the
origi nal work is p roper ly cited a nd is not use d for
commercial purposes (http://creativecommons.org/
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1Department of Orthopedic Surgery, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Achi, Japan
2Department of Orthopedic Surgery and Rheumatology, Nagoya University Graduate School of Medicine, Nagoya, Achi, Japan
3Department of Orthopedic Surgery, Aichi Medical University, Graduate School of Medicine, Nagakute, Aichi, Japan
Arch Rheumatol
16
Lifestyle changes have persisted even after
the COVID-19 pandemic, affecting daily habits
as well as social connections. These changes
are particularly concerning for individuals
with chronic conditions such as rheumatoid
arthritis (RA), where disease-specific factors
may further exacerbate vulnerabilities to frailty
and associated health issues. These patients are
more susceptible to frailty due to the chronic
inflammation and joint damage associated with
the disease.6 The percentage of RA patients
who experience frailty is believed to be higher
compared to the general population.6,7 With
significant advancements in RA treatment
through the use of methotrexate (MTX),
biologics, and Janus kinase inhibitors, the
survival of RA patients has improved.8 However,
as life expectancy increases, there is a greater
need to be vigilant about frailty, as the extended
lifespan can lead to a higher risk of functional
decline in these patients.
Rheumatoid arthritis patients are particularly
susceptible to dry mouth due to both systemic
effects and disease-related factors.9 Beyond
systemic manifestations, RA is associated with
oral function decline, including hyposalivation
and periodontal disease which are recognized as
non-articular manifestations of the condition.10
Several studies have indicated that RA patients
have a significantly higher risk of severe
periodontal disease compared to the general
population,10 highlighting the potential for oral
function decline to adversely affect overall
health and quality of life. In light of these
concerns, in the present study, we aimed to
explore the association between frailty and oral
function in RA patients.
PATIENTS AND METHODS
This multi-center, observational cohort study
(T-FLAG) was conducted at Japanese Red Cross
Aichi Medical Center Nagoya Daiichi Hospital,
Japan Community Health Care Organization
Kani Tono Hospital, and Yokkaichi Municipal
Hospital, Department of Orthopedic Surgery
between June 2023 and August 2023. A total
of 696 RA patients consecutively visited three
affiliated hospitals. Clinical data, including
Kihon Checklist (KCL) scores11 and Clinical
Disease Activity Index (CDAI),12 were available
for 661 of these patients. All patients met
the 2010 classification criteria established by
the American College of Rheumatology (ACR)
and the European League Against Rheumatism
(EUL AR).13 We did not establish formal exclusion
criteria for this study; however, patients with
missing data for either KCL score or CDAI were
excluded to ensure reliability of the dataset.
Finally, a total of 661 patients with complete data
(475 males, 186 females; mean age: 68.5±13.5
years; range, 18 to 100 years) were included in the
study. A written informed consent was obtained
from each patient. The study was approved by
the Ethics Committees of Nagoya University
School of Medicine (2017-0271), the Japanese
Red Cross Aichi Medical Center Nagoya Daiichi
Hospital (2020-451), the Japan Community
Health Care Organization Kani Tono Hospital
(20110901), and Yokkaichi Municipal Hospital
(2017-29), (date: 01.06.2020). The study was
conducted in accordance with the principles of
the Declaration of Helsinki.
Documented characteristics included age,
duration of disease, sex, body mass index (BMI),
marital status, smoking status, alcohol intake,
Steinbrocker classification stage (evaluated
at the most progressed joint),14 drug therapy
(glucocorticoids [GCs], MTX, other conventional
synthetic disease-modifying antirheumatic drugs
[csDMARDs] including salazosulfapyridine,
tacrolimus, bucillamine, and iguratimod, all of
which are approved and commonly used for
the treatment of RA in Japan,15 and biological
DMARDs [bDMARDs]/targeted synthetic
DMARDs [tsDMARDs]), diabetes mellitus (DM),
osteoporosis, Charlson Comorbidity Index
(CCI),16 rheumatoid factor (RF), C-reactive
protein (CRP), matrix metalloproteinase-3
(MMP-3), swollen and tender 28-joint count,
subject’s global assessment of disease activity
Visual Analog Scale (VAS), physician’s global
assessment of disease activity VAS, CDAI,
Health Assessment Questionnaire-Disability
Index (HAQ-DI),17 grip strength on the dominant
side (i.e., side with the higher value), laughter
frequency (almost every day/1 to 5 days per
week/1 to 3 days per month/never or almost
never),18 and the KCL. The CDAI was classified
as follows: remission (CDAI ≤2.8); low disease
activity (LDA; 2.8< CDAI ≤10); moderate disease
17
Frailty and oral function in RA
activity (MDA; 10< CDAI ≤22); and high disease
activity (HDA; CDAI >22).12 The daily frequency
of laughter was measured using a standard
single-item question: “How often do you laugh
out loud?”18 “Almost every day” and “1-5 days
per week” were defined as “frequent laughter,”
and “1-3 days per month” and “never or almost
never” were defined as “infrequent laughter”.19
Definition of frailty and oral function
decline
Frailty categories were determined using
KCL scores, with ≥8 points indicating frailty,
4-7 points indicating pre-frailty, and 0-3 points
indicating robustness. The KCL is a widely
utilized tool developed by Ministry of Health,
Labour and Welfare of Japan to identify older
adults at risk of needing care or support.11 The
KCL consists of a total of 25 Yes/No questions,
covering seven distinct domains. The domain
“Activities of daily living” includes Question
Nos. 1-5; “Physical strength” includes Question
Nos. 6-10; “Nutrition” includes Question Nos.
11 and 12; “Oral function” includes Question
Nos. 13-15; “Isolation” includes Question
Nos. 16 and 17; “Cognitive function” includes
Question Nos. 18-20; and “Depressive mood”
includes Question Nos. 21-25. Studies have
shown that the KCL is significantly correlated
with Fried’s Cardiovascular Health Study criteria,
confirming its validity as a screening instrument
to assess frailty.1,11
Oral function was assessed based on Questions
13 (“difficulty eating hard foods”), 14 (“choking
on tea or soup”), and 15 (“dry mouth”) of
the KCL. These questions were chosen, as
they address critical aspects of oral health that
are closely associated with nutrition, swallowing
ability, and salivary function. Declines in these
functions are commonly observed in older adults,
particularly those with RA, and have been shown
to significantly impact physical health, nutritional
status, and overall quality of life.20 A score of
≥2 was defined as oral function decline.11, 21 The
simplicity and practicality of these items make
them highly suitable for use in both clinical
and research settings, facilitating consistent and
efficient data collection.
Missing data
The breakdown of missing data (final
numbers and percentages in parentheses) is as
follows: three for BMI (658/661, 99.5%), six
for married (655/661, 99.1%), 242 for smoking
(419/661, 63.4%), 247 for alcohol intake
(414/661, 62.6%), five for RF (656/661, 99.2%),
two for CRP (659/661, 99.7%), seven for MMP3
(654/661, 98.9%), and nine for grip strength
(652/661, 98.6%).
Statistical analysis
Statistical analysis was performed using the
EZR (Saitama Medical Center, Jichi Medical
University, Saitama, Japan; http://www.jichi.
ac.jp/saitama-sct/SaitamaHP.files/statmed.
html), a graphical user interface for R software
(R Foundation Statistical Computing, Vienna,
Austria).22 Continuous variables were expressed
in mean and standard deviation (SD) or median
(min-max), while categorical variables were
expressed in number and frequency. The
Kruskal-Wallis test or Mann-Whitney U test
were used to analyze continuous variables.
Categorical variables were analyzed using the
Fisher exact test. Proportions of patients with
each oral function score (total score from
Questions 13 to 15 in the KCL) by age
group, CDAI category, and frailty status were
calculated and analyzed using the Cochran-
Armitage trend test. Correlations between
KCL categories were analyzed using the
Spearman rank correlation coefficient. Receiver
operating characteristic (ROC) curves were
generated to assess the association between
frailty and oral function scores. The most
optimal cut-off point was identified as the
maximum point of the Youden index, which
was calculated using the following formula:
Youden index = sensitivity + specificity – 1.
Multivariate logistic regression analyses were
performed to confirm the independent impact
of variables on oral function decline. To
further address potential confounding factors,
propensity score matching was performed to
balance variables, as informed by the results
of multivariate logistic regression analyses.
A p value of <0.05 was considered statistically
significant.
RESULTS
Table 1 presents the characteristics of
participants according to their oral function
score (i.e., total score from Questions
Arch Rheumatol
18
Table 1. Demographics and clinical characteristics of patients according to scores from questions 13 to 15 of the Kihon Checklist
Oral function scores (total score from questions 13 to 15 of the KCL)
0 points (n=271) 1 point (n=204) 2 points (n=137) 3 points (n=49) Tot a l (n=661)
Vari abl es %Mean±SD %Mean±SD %Mean±SD %Mean±SD %Mean±SD p
Age (year) 64.4±14.5 68.5±1 2.7 73.8±11.0 76.2±9. 3 68.5±13.5 <0.001
Duration of disease (year) 11.2±9.3 13.0 ±9.9 14.8±10.8 13 .4±10.3 1 2.7±10.0 0.002
Sex
Female 73.1 69.0 73.0 73.5 71.8
0.757
BMI (kg/m2)22 .2±3 .7 22 .1± 3.9 22.2±3.9 21.7± 3.2 22.2±3.8 0.914
Married 65.9 69. 5 55.9 57.1 64.3 0.0 47
Smoking (yes) 18.7 17.1 11.0 26.7 17.0 0.181
Alcohol intake
Regular
Occasional
No
17.4
19.9
62.7
13.9
22.1
63.9
12.9
10.9
76.2
10.0
10.0
80.0
14.7
17.6
67. 6
0.14 4
Steinbrocker stage
1
2
3
4
45.3
24.2
12.1
18.5
38.9
21.7
15.3
24.1
24.1
27. 7
19.0
29.2
28.6
26.5
20.4
24.5
37.6
24.3
15.1
22.9
0.009
Glucocorticoid use 20.3 35.8 29.2 3 6.7 2 8.1 0.001
Methotrexate use 64.9 62.7 5 0.4 57.1 60.7 0.032
Other csDMARD use 44.6 45.1 44.5 38.8 44.3 0.879
bDMARD use 30.6 34.8 33.6 3 4.7 32.8 0.78 5
tsDMA RD use 7.4 9. 8 12.4 12.2 9.5 0.3 61
Diabetes mellitus 6.6 8.3 12.4 20.4 9.4 0.011
Osteoporosis 18.5 22.5 31.4 32 .7 23.5 0.012
Charlson comorbidity index 1.4±0.7 1.5±0.8 1.7±1.0 1.7±0 .9 1.5±0.8 0.001
Rheumatoid factor positive 65.2 66.5 67. 2 61.2 6 5.7 0.884
CRP (mg/dL) 0.3±0.6 0.4±0.9 0.3±0.5 0.4±0.6 0.4±0.7 0.598
MMP-3 (ng/mL) 98.2±104.2 117.6±140.6 101. 3±78. 2 112 .9± 83 .3 105.9±111.1 0.072
Swollen joint count 0.6 ±1.7 1.0±2 .9 1.0±2.9 1.0±1.8 0.8±2.4 0.104
Tender joint count 1.2±2 .6 1.6±3.2 2. 2± 3.7 1.9± 4.1 1.6 ±3.2 0.008
Subject's assessment of pain VAS (mm) 15.5±22.3 20.7±23.8 27.2±26.8 31.2±31.5 2 0.7±2 5. 0 <0.001
Subject's global assessment of disease activity VAS (mm) 15.1±21.4 21.4±23.8 28.7±28.3 33 .0± 31.9 21.2±25.3 <0.001
19
Frailty and oral function in RA
Table 1. Continued
Oral function scores (total score from questions 13 to 15 of the KCL)
0 points (n=271) 1 point (n=204) 2 points (n=137) 3 points (n=49) Tot a l (n=661)
Vari abl es %Mean±SD %Mean±SD %Mean±SD %Mean±SD %Mean±SD p
Physician's global assessment of disease activity VAS (mm) 13.9±18.6 18.5±20.5 22.9 ±21. 8 24.9±24.8 18.0± 20.7 <0.001
CDAI 4 .7±6 .3 6.5±8.1 8.3±8.2 8.7±9. 3 6 .3±7.7 <0.0 01
HAQ-DI 0.27±0.52 0.49±0.66 0.78±0.7 7 1.09±0.92 0.51±0.70 <0.0 01
Grip strength (kg) 21.7±9.9 20.0±10.0 16. 2±8.1 16.6±8.6 19.6±9.7 < 0.0 01
Laughter frequency
Almost every day
1-5 days per week
1-3 days per month
Never or almost never
56.1
32.1
6.3
5.5
51.5
34.8
8.8
4.9
43.1
38.7
10.9
7.3
16.3
40.8
26.5
16.3
49.0
35.0
9.5
6.5
<0.0 01
KCL 4.0±3.6 7.0±4.0 10.6±4.6 13.8±4.3 7.0 ±5.1 <0.001
Question 13: Difficu lty in eating hard foods (yes) 022.5 61.3 100 2 7.1 <0.0 01
Question 14: Choking on tea or soup (yes) 029.9 62.8 100 2 9.7 <0.001
Question 15: Dry mout h (yes) 047. 5 75.9 10 0 3 7.9 < 0.0 01
Frailty 14 .8 38.2 70.8 93 .9 39.5 <0.001
KCL: The Ki hon Check list; SD: Standa rd devi ation; BM I: Body ma ss index; csDMARD: Conventional synt hetic diseas e-modifying antirhe umatic drugs; bDMAR D: Biolog ical DM ARD; t sDMA RD: Targeted synthet ic
DMAR D; CRP: C-reactiv e protein; MMP-3: Matri x metalloproteinase-3; VAS: Vis ual Anal og Scale; CDAI: Clinical Dise ase Activ ity Index; H AQ-DI: Heal th Assessment Que stionnaire-D isability Inde x; Frailt y, KCL ≥8
points; O ther (D MAR Ds) including s alazo sulfapyridi ne, tacrolimus, b ucillamine, a nd iguratimo d; P<0.05 was considered stat istic ally significant. P-va lues are from compa rison s among the four groups using t he Kruskal-
Wallis test and Fi sher exact test.
Arch Rheumatol
20
13 to 15 of the KCL). A total of 661 participants
were included, of which 261 (39.5%) were
classified as frail. The distribution of oral function
scores was as follows: 0 points for 271 patients,
1 point for 204 patients, 2 points for 137 patients,
and 3 points for 49 patients. Age, HAQ-DI, the
KCL, and frailty rates tended to increase with
higher scores. Among oral function questions
(Questions 13-15), “Dry mouth” (Question 15)
had the highest proportion in the group with an
oral function score of 1 point, affecting 47.5% of
the patients. In the group with a score of 2 points,
“Dry mouth” was observed in 75.9% of the
patients, while the proportions of “Difficulty in
eating hard foods” (Question 13) and “Choking”
(Question 14) were similar to each other at 61.3%
and 62.8%, respectively.
Figures 1a-c show proportions of patients
with each oral function score by age group,
CDAI category, and frailty status, respectively.
The proportion of patients with oral function
decline (oral function score ≥2 points) was
significantly lower in patients aged <60 years
compared to those aged ≥80 years (13.9%
and 50.3%, respectively; p<0.001), in those
in remission compared to those with HDA
(20.6% and 46.4%, respectively; p<0.001), and
in those who were robust in frailty status
compared to those who were frail (1.6% and
54.8%, respectively; p<0.001), as assessed by
the Cochran-Armitage trend test.
Table 2 presents correlation coefficients
(r) between KCL categories. The strongest
associations with oral function were observed
for physical strength (r=0.437, p<0.001) and
depressive mood (r=0.425). For total KCL score,
the strongest correlations, in descending order,
were with physical strength (r=0.797), depressive
mood (r=0.764), and activities of daily living
(r=0.662), with oral function (r=0.616) ranking
fourth.
In the ROC curve analysis for frailty, the
AUC was 0.790 (95% confidence interval
[CI]: 0.756-0.824) for the oral function score
(Figure 2). The optimal cut-off score for the
oral function score corresponding to frailty
was 2 points, with a specificity of 89.2% and
a sensitivity of 54.8%, corresponding to the
definition of oral function decline (i.e., total score
of ≥2 for Questions 13 to 15 of the KCL).
Using the above cut-off score, multivariate
logistic regression was conducted to identify
factors associated with oral function decline.
As shown in Table 3, oral function decline was
significantly associated with age (odds ratio
Figure 1. Proportions of patients with each score of oral function (total score from Questions 13 to 15 in the KCL) by
(a) age group, (b) CDAI category, and (c) frailty status. * p<0.001 by Cochran-Armitage trend test.
KCL: The Kihon Checklist; CDA I: Clinical Dis ease Activit y Index.
21
Frailty and oral function in RA
[OR]=1.06 [95% CI: 1.04-1.08]) and HAQ-DI
(OR=1.06 [95% CI: 1.03-1.10] per 0.1-point
increase) in both Model 1 (including DM and
osteoporosis as factors) and Model 2 (including
CCI as a composite factor). For “infrequent
laughter,” Models 1 and 2 showed an OR of 1.67
[95% CI: 1.00-2.76] and 1.68 [95% CI: 1.02-
2.79], respectively, both indicating a significant
association. To further confirm these findings,
propensity score matching was performed to
adjust for potential confounding factors, including
disease duration, sex, BMI, CDAI, GC use, MTX
use, and CCI (Table 4). The logistic regression
model incorporating propensity score as a
covariate demonstrated consistent results, with
significant associations between oral function
decline and age (OR=1.04 [95% CI: 1.02-1.06])
and HAQ-DI (OR=1.07 [95% CI: 1.03-1.10]), and
a marginal association between oral function
decline and infrequent laughter (OR=1.52 [95%
CI: 0.85-2.73]).
DISCUSSION
To the best of our knowledge, the present
study is the first to investigate the association
Table 2. Association between KCL categories
Oral function
(questions 13-15)
Activities of daily living
(questions 1-5)
Physical strength
(questions 6-10)
Nutrition
(questions 11-12)
Isolation
(questions 16-17)
Cognitive function
(questions 18-20)
Depressive mood
(questions 21-25)
Vari abl es rprprprprprprp
Activities of daily living 0.238 <0.0 01 - - ----------
Physical strength 0.437 <0.001 0.417 <0.0 01 ----------
Nutrition 0.070 0.073 0.101 0.009 0.119 0.002 --------
Isolation 0.272 <0.001 0.382 <0.001 0.444 <0.0 01 0.114 0.0 03 ------
Cognitive function 0.259 <0.0 01 0.258 <0.001 0.294 <0.001 0.021 0.587 0.270 <0.0 01 ----
Depressive mood 0.425 <0.0 01 0.376 <0.0 01 0.470 <0.001 0.101 0.009 0.446 <0.001 0.363 <0.001 - -
Total KCL score 0.616 <0.001 0.662 <0.001 0.79 7 <0.001 0.231 <0.001 0.600 <0.0 01 0. 514 <0.0 01 0.764 <0.0 01
KCL: The Ki hon Check list; r: Correlat ion coefficient; P<0.05 was conside red stat istic ally si gnificant.
Figure 2. ROC curves for frailty and oral function score
(total score from Questions 13 to 15 in the KCL). The
area under curve was 0.790 (95% CI: 0.756-0.824) and
the cut-off value was 2 points (specificity 89.2%; sensitivity
54.8%).
ROC: Receiver operating characterist ic; KCL: The K ihon Checklist;
CI: Confidence interval.
1.0
0.8
0.6
0.4
0.2
0.0
1.0 0.6 0.20.8 0.4 0.0
Specificity
Sensitivit y
Arch Rheumatol
22
between frailty and oral function in RA patients.
Our study showed a tendency for frailty to
increase with declining oral function and that the
proportion of patients with oral function decline
significantly increased with frailty. A cut-off
score of ≥2 for oral function was identified
as having high specificity (89.2%) according
to the ROC curve analysis, indicating that
patients with this score are more likely to be
frail, offering a straightforward and accessible
tool to facilitate early detection of frailty in
clinical settings. Oral function decline was
significantly associated with HAQ-DI, a measure
of physical function, as demonstrated in both the
multivariate logistic regression analysis and the
propensity score-adjusted model. This consistent
result highlights the robust relationship between
oral function decline and physical function. The
findings of the present study collectively suggest
the importance of monitoring oral function,
since it not only reflects physical function, but
also serves as a practical marker for identifying
frailty in RA patients. Incorporating oral function
assessments into routine RA management can
help healthcare providers identify patients at
higher risk of frailty and implement targeted
interventions to mitigate this risk, potentially
improving long-term patient outcomes.
The relationship between oral function and
physical function remains unclear in terms of
which influences the other. Oral frailty, defined
as a decline in three or more of six oral measures
(remaining teeth, chewing, tongue pressure, oral
motor skills, eating difficulty, and swallowing),
Table 3. Odds ratios for oral function decline by multivariate logistic regression analyses
Model 1 Model 2
Vari abl es OR 95% CI pOR 95% CI p
Age (year) 1.06 1.0 4-1.08 < 0.001* 1.0 6 1.04-1.08 < 0.0 01*
Duration of disease (year) 0.99 0 .9 6 -1.01 0.234 0.98 0.9 6 -1.01 0.206
Sex
Female 1.0 6 0. 62-1 .82 0.820 1.07 0.6 3 -1. 81 0.79 5
BMI (kg/m2)1.01 0 .9 6 -1. 07 0.721 1.01 0.9 6 -1. 07 0.635
Married 0.74 0 . 50-1.11 0.14 3 0.77 0. 51-1.15 0 .195
Steinbrocker stage (3/4) 1.19 0.73 -1.95 0.477 1.21 0.74 -1 .9 6 0.450
Glucocorticoid use 0.78 0.50-1.20 0.256 0.78 0.51-1.20 0.262
Methotrexate use 0.90 0.58-1.38 0.618 0.95 0.61-1.49 0.824
Other csDMARD use 0.77 0 . 51-1.17 0.223 0.77 0 . 51-1.17 0.223
bDMARD use 1.03 0.66-1.62 0.889 1.05 0.67-1.65 0.835
tsDMA RD use 1.05 0.54-2.06 0.881 1.05 0.53-2.05 0.895
Diabetes mellitus 1.36 0.73-2.5 3 0.329 - - -
Osteoporosis 0.95 0.59-1.53 0.834 - - -
Charlson comorbidity index - - - 1.19 0.95 -1.4 8 0.140
Rheumatoid factor positive 0.83 0.5 5 -1.2 5 0.366 0.82 0. 5 4 -1. 2 3 0.328
CDAI 1.03 1.00 -1.06 0.054 1.03 0.9 9-1.06 0.070
Grip strength (kg) 0.99 0 .9 6 -1.02 0.477 0.9 9 0.96 -1.02 0.492
HAQ-DI 1.06 1.03 -1.10 <0.0 01* 1.06 1.03-1.10 <0.001*
Infrequent laughter (1-3 days per month/never or almost never) 1.67 1.00 -2 .76 0.04 8* 1.68 1.0 2-2.79 0.043*
OR: Odds ratio; CI: Confidence interval; BMI: Body mass index; csDMA RD: Conv entiona l synthetic di sease -modif ying a ntirheu matic drugs; bDM ARD: Biologi cal
DMAR D; tsDM ARD: Targete d synthetic DM ARD; CDA I: Clinical Di sease Activity Index; HAQ-DI: Health Asses sment Questio nnaire -Disab ility I ndex. Or al
funct ion decli ne, oral function score (from q uestions 13 to 15 in the Kihon Checkli st) ≥2 points; Odds ratio for 0.1 point inc rease in HAQ-DI. * p<0.05 was
considered statistically significant.
23
Frailty and oral function in RA
has been reported to be significantly associated
with both physical frailty and mortality.23 In older
adults, a decline in oral function reportedly leads
to reduced protein intake.24 Typically, a decline in
oral function would affect nutritional intake and
the ability to eat properly, which can then lead
to reduced muscle strength and a subsequent
decline in overall physical function. However,
impaired physical function can also affect oral
function. The HAQ-DI, a physical function
index, is a significant indicator of sarcopenia in
RA patients.25 Sarcopenia, characterized by a
progressive loss of muscle mass and function,
affects not only the body’s skeletal muscles
but also masticatory and swallowing muscles,
thereby impairing oral function.20 It is likely that
oral function and physical function are mutually
related, making it difficult to clearly determine
which influences the other. In any case, as both
oral function and physical function inevitably
decline with age,20 it is crucial for older adults to
maintain these functions through comprehensive
monitoring and care.
Among KCL categories, “physical strength”
(Questions 6-10) and “depressive mood”
(Questions 21-25) were most strongly associated
with “oral function” (Questions 13-15). “Physical
strength” is assessed through questions
regarding the ability to walk, climb stairs,
and stand up from a chair, which are closely
related to items assessed with the HAQ-DI. The
assessment of “depressive mood” is based on
factors such as the lack of fulfillment, reduced
enjoyment, task difficulty, uselessness, and
Table 4. Demographics and clinical characteristics of patients by oral function decline status after propensity score
matching
Oral function scores (total score from
questions 13 to 15 of the KCL)
No oral function decline
0-1 points (n=172)
Oral function decline
2-3 points (n=172)
Vari abl es %Mean±SD %Mean±SD p
Age (year) 68 .3±14 .1 74. 0±10.7 <0.001
Duration of disease (year) 13.8±10.3 13.9±10.3 0.859
Sex
Female 71.5 73.3 0. 810
BMI (kg/m2)22.3±4.1 22.1±3 .6 0.889
Glucocorticoid use 29.7 29.7 1.000
Methotrexate use 54 .7 55.2 1.000
Charlson comorbidity index 1.7±0.9 1.6±0.8 0.401
CDAI 7. 2 ±7. 4 8.0±8.5 0.559
HAQ-DI 0.53±0.69 0.84±0.81 <0.0 01
Laughter frequency
Almost every day
1-5 days per week
1-3 days per month
Never or almost never
50.6
34.9
7.6
7.0
35.5
39.0
15.1
10.5
<0.0 01
KCL 6.1±4.5 11.3± 4.7 < 0.0 01
Question 13: Difficu lty in eating hard foods (yes) 13.4 70.9 <0.001
Question 14: Choking on tea or soup (yes) 14.5 73.8 <0.001
Question 15: Dry mout h (yes) 21.5 82 <0.001
Frailty 3 3.7 76.7 <0.001
KCL: The Ki hon Check list; SD: Standa rd devi ation; BM I: Body ma ss index; CDAI: Cli nical Disease Activ ity In dex; HAQ-DI: Health Assessment Quest ionnai re-
Disabi lity Ind ex. O ral func tion decli ne, oral func tion score (from quest ions 13 to 15 i n t he K ihon Check list) ≥2 points. Propensit y s core matching analysis was
conducted to adjus t for disease duration, sex, BMI, CDA I, gluco corticoid use, methotrexate use, and Charlson comorbidit y index.
Arch Rheumatol
24
fatigue. These factors were particularly relevant
during the COVID-19 pandemic, when there
were restrictions on going out and engaging in
social interactions. RA patients are more likely
to experience depressive symptoms than the
general population.26 Moreover, participants
living alone during the COVID-19 pandemic
experienced more negative emotions than those
living with relatives or spouses.27 Negative
emotions, such as depressive mood, further
reduce social interactions, leading to fewer
opportunities to use one’s voice. This may have
also contributed to a decline in oral function.
A significant association was also found
between oral function decline and infrequent
laughter. The muscles used for laughing are
reportedly the same as those involved in oral
function, such as swallowing and chewing
muscles.28 In addition, laughter temporarily
increases salivary immunoglobulin A (IgA) levels,
suggesting that laughter may enhance certain
aspects of immune function.29 Laughter is also
known to have positive effects on health30 and
has been shown to reduce stress hormones.31 In
a six-year follow-up cohort study, shared social
interactions, through laughter, were associated
more strongly with a reduced risk of functional
disability than laughing alone (e.g., laughing
while watching television).32 Conversely, a lack
of laughter has been associated with future
functional decline and mortality.33 These findings
highlight the importance of maintaining oral
function by creating social interactions through
laughter to support both emotional well-being
and physical health.
Frailty in RA patients is influenced by
systemic inflammation, which may also affect
oral function decline through molecular
pathways. Chronic inflammation in RA has
been associated with structural changes in
salivary glands, such as fibrosis, which can
impair salivary gland function, reduce mucin
production, and lead to hyposalivation.34
These changes may compromise the
protective functions of saliva, increasing the
susceptibility to infections and disrupting oral
immune components including salivary IgA.35
Salivary IgA plays a crucial role in mucosal
immunity by preventing microbial adhesion
and neutralizing pathogens, and alterations
in its levels are associated with an increased
risk of oral and systemic infections.35 Salivary
immune components have also been linked
to autoimmune conditions such as primary
Sjögren’s syndrome, in which interleukin (IL)-6,
to illustrate, correlates with disease activity
and mucosal immune responses.36 However,
specific involvement of these components in
RA-related oral dysfunction remains to be
fully elucidated. In addition to its direct effects
on oral health, systemic inflammation in RA,
driven by tumor necrosis factor-alpha (TNF-a)
and other inflammatory cytokines with catabolic
effects on skeletal muscle, contributes to muscle
loss (sarcopenia)37 which negatively impacts
mastication and swallowing muscles. This
cross-system interaction exacerbates difficulties
in chewing and swallowing, further contributing
to oral dysfunction. Moreover, oral dysfunction
may perpetuate systemic inflammation through
poor nutrition and increased susceptibility to
infections, creating a vicious cycle that worsens
health outcomes and promotes frailty. Future
studies should explore the role of inflammatory
biomarkers, such as IL-6 and TNF-a, to clarify
the complex relationships between systemic
inflammation, oral health, and frailty in RA
patients. Understanding these molecular
pathways will aid in the development of targeted
therapeutic strategies to address both systemic
and oral inflammation, ultimately reducing
frailty and improving patient outcomes.
Building on these findings, targeted
interventions could help mitigate oral function
decline and its impact on frailty in RA
patients. Regular oral function assessments
could be seamlessly integrated into standard
RA management workflows, providing
valuable insights into both physical and frailty-
related risks. Such integration would enable
personalized care plans, including physical and
oral rehabilitation programs, to address the
multifaceted challenges faced by RA patients.
Programs such as COPE-TeL, a comprehensive
oral and physical exercise program including
textured lunch gatherings, have demonstrated
significant benefits in improving oral health
and overall physical well-being among older
adults with oral function decline.38 Similarly,
progressive lingual resistance exercises have
been shown to enhance tongue strength and
swallowing function, addressing key aspects
25
Frailty and oral function in RA
of oral function decline.39 Implementing such
interventions in RA management could improve
both physical and emotional well-being, reduce
the risk of frailty, and enhance the quality of life
for these patients.
Nonetheless, the present study has several
limitations. First, there was no evaluation of
oral function specifically related to oral frailty,
such as swallowing function tests (e.g., water
swallowing test, repetitive saliva swallowing
test). Second, as this is a cross-sectional study,
causal relationships between associated factors
remain unclear. Third, while the study was
conducted during the COVID-19 pandemic, i.e.,
a period influenced by lifestyle changes, data on
participants’ infection status or its direct effects
were not collected.
In conclusion, an oral function score of
≥2 points, based on Questions 13-15 of the
KCL (i.e., difficulty eating hard foods, choking,
and dry mouth), strongly indicates a higher
likelihood of frailty in RA patients. Thus, this
score may serve as a simple and accessible
marker of frailty, enabling early detection in
clinical practice. Moreover, oral function decline
was closely associated with physical function,
as measured by HAQ-DI, highlighting the
interconnectedness of oral and physical health.
These results underscore the importance of
routine monitoring of oral function, which could
be seamlessly integrated into clinical workflows
to facilitate early identification of frailty and guide
targeted interventions. Promoting oral health
and physical resilience through comprehensive
strategies, including interventions to foster
laughter, to illustrate, may help mitigate the risk
of frailty in RA patients. Further longitudinal
studies are warranted to explore the relationship
between physical and oral function in relation to
frailty and to clarify causal relationships between
these factors.
Acknowledgments: We thank Dr. Koji Funahashi,
Dr. Hiroshi Koshima, Dr. Nobuyuki Okui, Dr. Hisato
Ishikawa, Ms. Sachiko Kato, Ms. Emi Yokota, Ms. Ritsuko
Otake, and Ms. Takako Sashikata for their assistance in
information collection.
The authors also thank ChatGPT for assistance
with writing and spelling corrections. The responsibility
for the content accuracy, data interpretation, and final
approval of the manuscript rests solely with the authors.
Additionally, the authors received English language
editing services from ProEdit Japan, Inc.
Data Sharing Statement: The data that support the
findings of this study are available from the corresponding
author upon reasonable request.
Author Contributions: Idea/concept, design,
control/supervision, data collection and/or processing,
analysis and/or interpretation, literature review, writing the
article, and critical review: Y.S., M.S., Y.O.; Contributed
to data collection and/or processing and critical review:
R.S., Y.O., J.H., T.S., K.T., S.A.; Control/supervision,
idea/concept, design, and critical review: S.I. All authors
read and approved the final manuscript.
Conflict of Interest: The authors declared no
conflicts of interest with respect to the authorship and/or
publication of this article.
Funding: The authors received no financial support
for the research and/or authorship of this article.
REFERENCES
1. Fried LP, Tangen CM, Walston J, Newman AB,
Hirsch C, Gottdiener J, et al. Frailty in older
adults: Evidence for a phenotype. J Gerontol A
Biol Sci Med Sci 2001;56:M146-56. doi: 10.1093/
gerona/56.3.m146.
2. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K.
Frailty in elderly people. Lancet 2013;38:752-62. doi:
10.1016/S0140 - 6736 (12) 62167-9.
3. Kontis V, Bennett JE, Mathers CD, Li G, Foreman K,
Ezzati M. Future life expectancy in 35 industrialised
countries: Projections with a Bayesian model
ensemble. Lancet 2017;389:1323-35. doi: 10.1016/
S0140-6736(16)323 81-9.
4. Hewitt J, Carter B, Vilches-Moraga A, Quinn TJ,
Braude P, Verduri A, et al. The effect of frailty
on survival in patients with COVID-19 (COPE): A
multicentre, European, observational cohort study.
Lancet Public Health 2020;5:e444-51. doi: 10.1016/
S2468-2667(20)30146-8.
5. Sobue Y, Suzuki M, Ohashi Y, Koshima H, Okui
N, Funahashi K, et al. Locomotive syndrome in
rheumatoid arthritis patients during the COVID-19
pandemic. Nagoya J Med Sci 2022;84:799-812. doi:
10.18999/nagjms.84.4.799.
6. Sobue Y, Suzuki M, Ohashi Y, Koshima H, Okui N,
Funahashi K, et al. Relationship between locomotive
syndrome and frailty in rheumatoid arthritis patients
by locomotive syndrome stage. Mod Rheumatol
2022;32:546-53. doi: 10.1093/mr/roab024.
7. Tada M, Yamada Y, Mandai K, Hidaka N. Correlation
between frailty and disease activity in patients with
rheumatoid arthritis: Data from the CHIKARA study.
Geriatr Gerontol Int 2019;19:1220-5. doi: 10.1111/
gg i.13795.
Arch Rheumatol
26
8. Zhang Y, Lu N, Peloquin C, Dubreuil M, Neogi
T, Aviña-Zubieta JA, et al. Improved survival in
rheumatoid arthritis: A general population-based
cohort study. Ann Rheum Dis 2017;76:408-13. doi:
10.1136/annrheumdis-2015-209058.
9. Conforti A, Di Cola I, Pavlych V, Ruscitti P,
Berardicurti O, Ursini F, et al. Beyond the joints, the
extra-articular manifestations in rheumatoid arthritis.
Auto immu n Rev 2021;20:10273 5. doi: 10.1016/ j.
autrev.2020.102735.
10. González DA, Bianchi ML, Armada M, Escalante
AC, Salgado PA, Seni S, et al. Hyposalivation and
periodontal disease as oral non-articular characteristics
in rheumatoid arthritis. Clin Rheumatol 2024;43:95-
102. d oi: 10.1007/s10067-023- 06718-1.
11. Satake S, Senda K, Hong YJ, Miura H, Endo H,
Sakurai T, et al. Validity of the Kihon Checklist
for assessing frailty status. Geriatr Gerontol Int
2016;16:709 -15. doi: 10.1111/ggi .12 5 43.
12. Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH,
Funovits J, et al. American College of Rheumatology/
European League against Rheumatism provisional
definition of remission in rheumatoid arthritis for
clinical trials. Ann Rheum Dis 2011;70:404-13. doi:
10.113 6/a r d.2 011.14976 5.
13. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson
DT, Bingham CO 3rd, et al. 2010 Rheumatoid
arthritis classification criteria: An American College
of Rheumatology/European League Against
Rheumatism collaborative initiative. Arthritis Rheum
2010;62:2 569-81. do i: 10.1002/a r t.2 75 84.
14. Steinbrocker O, Traeger CH, Batterman RC.
Therapeutic criteria in rheumatoid arthritis. J
Am Med Assoc 1949;140:659-62. doi: 10.1001/
jama.1949.02900430001001.
15. Nakayama Y, Nagata W, Takeuchi Y, Fukui S, Fujita
Y, Hosokawa Y, et al. Systematic review and meta-
analysis for the 2024 update of the Japan College
of Rheumatology clinical practice guidelines for the
management of rheumatoid arthritis. Mod Rheumatol
2024;34:1079-94. doi: 10.1093/m r/ro ae0 49.
16. Charlson ME, Pompei P, Ales KL, MacKenzie CR.
A new method of classifying prognostic comorbidity
in longitudinal studies: Development and validation.
J Chronic Dis 1987;40:373-83. doi: 10.1016/0021-
9681(87)90171-8.
17. Pincus T, Summey JA, Soraci SA Jr, Wallston KA,
Hummon NP. Assessment of patient satisfaction in
activities of daily living using a modified Stanford
Health Assessment Questionnaire. Arthritis Rheum
198 3;26:134 6 -53. doi: 10.1002 /ar t.1780261107.
18. Hayashi K, Kawachi I, Ohira T, Kondo K, Shirai K,
Kondo N. Laughter is the best medicine? A cross-
sectional study of cardiovascular disease among older
Japanese adults. J Epidemiol 2016;26:546-52. doi:
10.2188/j ea. J E20150196.
19. Suzuki M, Kojima T, Terabe K, Ohashi Y, Sato R,
Kosugiyama H, et al. Association between laughter,
frailty, and depression in rheumatoid arthritis patients.
Int J Rheum Dis 2024;27:e15034. doi: 10.1111/1756-
185X.15 034.
20. Dibello V, Zupo R, Sardone R, Lozupone M, Castellana
F, Dibello A, et al. Oral frailty and its determinants
in older age: A systematic review. Lancet Healthy
Longev 2021;2:e507-20. doi: 10.1016/S2666-
7568 (21)00143-4.
21. Tamada Y, Takeuchi K, Kusama T, Saito M, Ohira
T, Shirai K, et al. Reduced number of teeth with
and without dental prostheses and low frequency
of laughter in older adults: Mediation by poor oral
function. J Prosthodont Res 2024;68:441-8. doi:
10.2186/jpr.JPR_D_23_00071.
22. Kanda Y. Investigation of the freely available easy-
to-use software ‘EZR’ for medical statistics. Bone
Marrow Transplant 2013;48:452-8. doi: 10.1038/
bmt.2012.244.
23. Tanaka T, Takahashi K, Hirano H, Kikutani T,
Watanabe Y, Ohara Y, et al. Oral frailty as a risk
factor for physical frailty and mortality in community-
dwelling elderly. J Gerontol A Biol Sci Med Sci
2018;73:1661-7. doi: 10.1093/gerona/glx225.
24. Iwasaki M, Yoshihara A, Ogawa H, Sato M, Muramatsu
K, Watanabe R, et al. Longitudinal association of
dentition status with dietary intake in Japanese adults
aged 75 to 80 years. J Oral Rehabil 2016;43:737-44.
do i: 10.1111/joo r.12427.
25. Sobue Y, Suzuki M, Ohashi Y, Sato R, Kosugiyama
H, Ohno Y, et al. Association between sarcopenia
and locomotive syndrome in rheumatoid arthritis
patients: A multicenter observational study (T-FLAG).
Int J Rheum Dis 2024;27:e15321. doi: 10.1111/1756-
185X.15321.
26. Matcham F, Rayner L, Steer S, Hotopf M. The
prevalence of depression in rheumatoid arthritis: A
systematic review and meta-analysis. Rheumatology
(Oxford) 2013;52:2136-48. doi: 10.1093/
rheumato logy/ke t169.
27. Caillot-Ranjeva S, Bergua V, Meillon C, Amieva
H. Impact of cohabitation during confinement on
older adults' negative affect: What specificity of life
as a couple? J Frailty Aging 2024;13:64-70. doi:
10.14283/jfa.2023.25.
28. Belyk M, McGettigan C. Real-time magnetic resonance
imaging reveals distinct vocal tract configurations
during spontaneous and volitional laughter. Philos
Trans R Soc Lond B Biol Sci 2022;377:20210511.
doi: 10.1098/rstb.2021.0511.
29. Bennett MP, Lengacher C. Humor and laughter may
influence health IV. humor and immune function. Evid
Based Complement Alternat Med 2009;6:159-64.
doi: 10.10 93/ec a m/nem149.
30. H irosaki M, Ohira T, Kajiura M, Kiya ma M, Kitamura A,
Sato S, et al. Effects of a laughter and exercise program
on physiological and psychological health among
community-dwelling elderly in Japan: Randomized
controlled trial. Geriatr Gerontol Int 2013;13:152-60.
doi: 10.1111/j.1447-0594.2012.00877.x.
27
Frailty and oral function in RA
31. Berk LS, Tan SA, Fry WF, Napier BJ, Lee JW,
Hubbard RW, et al. Neuroendocrine and stress
hormone changes during mirthful laughter. Am J
Med Sci 1989;298:390-6. doi: 10.1097/00000441-
198912000-00006.
32. Tamada Y, Yamaguchi C, Saito M, Ohira T, Shirai
K, Kondo K, et al. Does laughing with others
lower the risk of functional disability among older
Japanese adults? The JAGES prospective cohort
study. Prev Med 2022;155:106945. doi: 10.1016/j.
ypmed.2021.106945.
33. Tamada Y, Takeuchi K, Yamaguchi C, Saito M,
Ohira T, Shirai K, et al. Does laughter predict onset
of functional disability and mortality among older
Japanese adults? The JAGES Prospective Cohort
Study. J Epidemiol 2021;31:301-7. doi: 10.2188/jea.
JE20200051.
34. Katona K, Farkas N, Kneif M, SütŐ G, Berki T,
Balatonyi B, et al. Image analysis of fibrosis in labial
salivary glands of patients with systemic autoimmune
diseases. Close correlation of lobular fibrosis to
seropositive rheumatoid arthritis and increased
anti-CCP and RF titres in the serum. Pathology
2018;5 0:418-25. doi: 10.1016/j.pat hol.2017.12.339.
35. Jankowski J, Nijakowski K. Salivary immunoglobulin
a alterations in health and disease: A bibliometric
analysis of diagnostic trends from 2009 to 2024.
Antibodies (Basel) 2024;13:98. doi: 10.3390/
ant i b13 0 40098 .
36. Hung YH, Lee YH, Chen PP, Lin YZ, Lin CH, Yen
JH. Role of salivary immune parameters in patients
with primary Sjögren's syndrome. Ann Lab Med
2019;39:76-8 0. doi: 10.33 43/a lm.2019.39.1.76.
37. Schaap L A, Pluijm SM, Deeg D J, Harris TB, K ritchevsky
SB, Newman AB, et al. Higher inflammatory marker
levels in older persons: Associations with 5-year
change in muscle mass and muscle strength. J
Gerontol A Biol Sci Med Sci 2009;64:1183-9. doi:
10.1093/gerona/glp097.
38. Matsuo K, Kito N, Ogawa K, Izumi A, Kishima M,
Itoda M, et al. Improvement of oral hypofunction by a
comprehensive oral and physical exercise programme
including textured lunch gatherings. J Oral Rehabil
2021;48:411-21. doi : 10.1111/j oor.1312 2.
39. Robbi ns J, Gangnon RE , Theis SM, Kays SA , Hewitt AL ,
Hind JA. The effects of lingual exercise on swallowing
in older adults. J Am Geriatr Soc 2005;53:1483-9.
doi: 10.1111/j.1532-5415.2005.53467.x.
