Elsevier

Journal of Autoimmunity

Volume 59, May 2015, Pages 85-90
Journal of Autoimmunity

Short communication
Significant association of periodontal disease with anti-citrullinated peptide antibody in a Japanese healthy population – The Nagahama study

https://doi.org/10.1016/j.jaut.2015.03.002Get rights and content

Highlights

  • Positivity and levels of ACPA are associated with PD status in healthy population.

  • However, positivity and levels of RF are not associated with PD status.

  • PD is suggested to be involved with production of ACPA.

Abstract

Anti-citrullinated peptide antibody (ACPA) is a highly specific autoantibody to rheumatoid arthritis (RA). Recent studies have revealed that periodontal disease (PD) is closely associated with RA and production of ACPA in RA. Analyses of associations between PD and ACPA production in a healthy population may deepen our understandings. Here, we analyzed a total of 9554 adult healthy subjects. ACPA and IgM-rheumatoid factor (RF) was quantified and PD status was evaluated using the number of missing teeth (MT), the Community Periodontal Index (CPI) and Loss of Attachment (LA) for these subjects. PD status was analyzed for its association with the positivity and categorical levels of ACPA and RF conditioned for covariates which were shown to be associated with PD, ACPA or RF. As a result, all of MT, CPI and LA showed suggestive or significant associations with positivity (p = 0.024, 0.0042 and 0.037, respectively) and levels of ACPA (p ≤ 0.00031), but none of the PD parameters were associated with those of RF. These association patterns were also observed when we analyzed 6206 non-smokers of the participants. The significant associations between PD parameters and positivity and levels of ACPA in healthy population support the fundamental involvement of PD with ACPA production.

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

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    These authors equally contributed to this work.

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