Short communicationSignificant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population – The Nagahama study
Introduction
Rheumatoid arthritis (RA) is the most common cause of adult chronic autoimmune arthritis in the world affecting 0.5–1.0% of the population. Environmental and genetic factors have been shown to be important for the onset of RA [1], [2]. Anti-citrullinated peptide antibody (ACPA) and rheumatoid factor (RF) are autoantibodies frequently found in patients with RA [3], [4], [5]. ACPA is a highly specific autoantibody to RA [5]. Smoking is an established environmental factor which is associated with RA development and ACPA positivity in RA [6], [7]. Although the pathological function of ACPA is not fully established, recent studies have revealed that some fractions of ACPA is pathogenic in experimental animal models [8].
The association between periodontal disease (PD) and RA development has been reported and PD is an emerging risk factor for RA [9]. PD affects more than 20% of the general population and its chronic inflammation leads to the damage of oral tissues including periodontal ligaments, resulting in periodontal pockets and ultimately, tooth loss [10]. Patients with RA were reported to have higher frequency of PD and severer PD than controls including patients with osteoarthirits [11], [12]. Since Porphyromonas gingivalis (P. gingivalis), a bacterial flora of PD, is the only microorganism ever found with citrullination enzyme peptidylarginine deiminase (PAD) [13], it has been hypothesized that PD is associated with the production of ACPA via citrullination of proteins by P. gingivalis and the resultant RA [14], [15]. However, it is difficult to assess whether PD is a cause or result of RA when analyzing data of patients with RA. In spite of a previous study reporting the presence of PD in patients with early RA naïve to DMARDs treatment [16], the possibility is undeniable that decreased activity of daily living due to early RA would lead to PD. Since RF and ACPA can be observed in patients with other diseases and even in healthy populations, studies should extend to healthy individuals to confirm the correlation between PD and production of RA-related autoantibodies and provide a clue to the causality of PD on the autoantibody production.
Recently, we reported detailed distribution and correlates of ACPA and RF using the data of the Nagahama Study, a Japanese community based prospective cohort [17]. Here, we analyzed the associations between PD status and RA-related autoantibodies especially ACPA using the data of the Nagahama study.
Section snippets
Study subjects
A total of 9804 subjects were registered in the Nagahama Study. 201 subjects were excluded due to having or being suspected to have autoimmune diseases. 28 subjects were excluded due to insufficient data. As a result, 9575 subjects in the Nagahama Study who did not have connective tissue diseases [17] were selected for the current study. The details of sample selections were described in the previous study [17]. The current study was approved by the Ethics Committee, Kyoto University Graduate
Associations between PD and positivity of RF or ACPA
A total of 9554 subjects were recruited from the 9804 participants in the Nagahama study. The characteristics of the 9554 study participants in the current study are summarized in Table 1 and detailed distributions of PD parameters are shown in Supplementary Table 3. In addition, we performed sub-analysis using 6206 non-smokers among the 9554 subjects. The detailed process of sample exclusion and study design are shown in Supplementary Fig. 1. Of the participants, 1.7 and 6.4% were positive for
Discussion
9575 healthy subjects without connective tissue diseases were selected in this study. The 201 subjects excluded from the current study due to possibility of having connective tissue diseases were 2.1% of the Nagahama Study participants and 27.9, 34.8 and 70.1% of them were positive for ACPA, RF, and anti-nuclear antibody, respectively. The percentage of excluded samples seems reasonable considering prevalence of RA and safety margin to avoid contamination of patients with RA in the current
Conclusions
ACPA positivity and levels are associated with PD in a healthy population. This association would support involvement of PD in the process of production of ACPA.
Conflict of interest
None.
Acknowledgment
We would like to thank all participants and members of the Nagahama study.
Funding statement: This study was supported by a University Grants and a Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan; the Program for Enhancing Systematic Education in Graduate School from the Japan Society for the Promotion of Science; a research grant from the Takeda Science Foundation, Japan. None of the funding sources was related to design and
References (24)
- et al.
Dentistry and internal medicine: from the focal infection theory to the periodontal medicine concept
Eur. J. Intern. Med.
(2010) - et al.
Oral health status among low-income people admitted to Osaka Socio-Medical Center in Japan
Int. Dent. J.
(2009) - et al.
Socioeconomic status and health in the Japanese population
Soc. Sci. Med.
(2009) Genetic contribution to susceptibility and disease phenotype in rheumatoid arthritis
Inflamm. Regen.
(2014)- et al.
Myelin basic protein as a novel genetic risk factor in rheumatoid arthritis–a genome-wide study combined with immunological analyses
PLoS One
(2011) - et al.
Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis
Ann. Intern. Med.
(2007) - et al.
Rheumatoid factor on a daily basis
Autoimmunity
(2005) - et al.
The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide
Arthritis Rheum.
(2000) - et al.
Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies
Ann. Rheum. Dis.
(2010) - et al.
A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination
Arthritis Rheum.
(2006)
Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis
J. Clin. Invest.
Accuracy of NHANES periodontal examination protocols
J. Dent. Res.
Cited by (37)
Periodontitis and periodontopathic bacteria as risk factors for rheumatoid arthritis: A review of the last 10 years
2023, Japanese Dental Science ReviewThe pathogenesis of rheumatoid arthritis
2022, ImmunityCitation Excerpt :Healthy individuals may develop low titers of ACPA associated with concomitant risk factors, e.g., smoking and periodontitis. In the absence of HLA-DR SE, these generally will not promote disease (Padyukov et al., 2004; Koning et al., 2015; Alpizar-Rodriguez et al., 2017; Terao et al., 2015). With HLA-SE, the presence of ACPA is associated with development of disease and thereafter, a more aggressive clinical course, with increased propensity to articular damage.
Autoimmune conditions and epigenetic challenges in periodontitis
2022, Translational Autoimmunity: Challenges for Autoimmune Diseases: Volume 5Upregulation of circulating inflammatory biomarkers under the influence of periodontal disease in rheumatoid arthritis patients
2020, CytokineCitation Excerpt :Several studies have reported a high PD prevalence in RA patients when compared to healthy controls [7]. Large cohort studies have also reported significant associations between PD parameters and positivity of ACPA, however, the mechanistic link and contribution of PD towards RA disease activity and inflammation is not clear [8]. Our study aimed to test the hypothesis that PD can exert substantial inflammatory burden which can additionally impact the rheumatological and systemic inflammatory profile of RA patients.
Detection of anti-citrullinated protein antibody (ACPA) in saliva for rheumatoid arthritis using DBA mice infected with Porphyromonas gingivalis
2019, Archives of Oral BiologyCitation Excerpt :PAD and PPAD citrullinate proteins such as vimentin that give rise to autoantibody ACPA. In a Nagahama cohort study in which approximately 10,000 healthy citizens who have not developed RA were followed for 5 years, the severity of periodontal disease is correlated with ACPA-positive rates, and RA is associated with periodontal disease (Terao et al., 2015). These reports suggest the relevance of periodontal disease in RA.
Human Microbiota and Autoimmune Diseases
2019, Mosaic of Autoimmunity: The Novel Factors of Autoimmune Diseases
- 1
These authors equally contributed to this work.