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Rheumatology 2015;54:22572263 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 casecontrol 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 27, 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 [14]. ! 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 [58]. 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 [912]. In particular, there are numerous studies reporting a strong association between RA and periodontal diseases [1315]. 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-CRPbased 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 [2426] 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 15 and proximal IP joints 15) 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 (014 mm/h), haemoglobin (Hb) (11.514.7 g/dl), MMP-3 (17.359.7 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, 2029 years) were calculated using the following equation. Standardized value ¼ IgG titre of patientmean 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 MannWhitney test for skewed variables was used. For group comparisons between three or four groups, the KruskalWallis 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 sulphadiazinetrimethoprim concomitantly with prednisolone. Sulphadiazinetrimethoprim 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, MannWhitney 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 (6475.5) 17 (81) 6 (2.7514.5) 61 (48.569) 35 (73) 8 (415) 57 (54.569.5) 19 (86) 3 (1.758.5) 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 KruskalWallis 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 (2.864.35) 4.77 (4.075.55) NT 0.17 (0.402.80) 37 (21.2552.25) 11.1 (10.412.75) 215.8 (106.4364.0) 119 (44699) 75.2 (10.2113.5) USPD (+) 0.00 1.45 2.00 9 0.07 10 13.1 53.5 17.5 32.6 (0.000.34) (1.161.70)** (1.512.59)** (714.75) (0.030.13)** (5.513)** (12.413.9)** (33.081.6)** (433)** (5.8163.0) 0.00 1.24 1.76 5 0.04 6 13.0 38.9 6 16.3 USPD () P-value (0.000.22) (1.051.76)** (1.282.20)** (27)**** (0.020.06)**,*** (4.7515)** (11.614.2)* (27.352.8)** (025.5)** (3.643) 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 KruskalWallis 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 [58], 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 [3134]. 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 [3638]. 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 www.rheumatology.oxfordjournals.org known to play a role in periodontal destruction in periodontitis [4143] 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 sulphadiazinetrimethoprim, 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. References 1 Weinblatt ME, Polisson R, Blotner SD et al. The effects of drug therapy on radiographic progression of rheumatoid arthritis. Results of a 36-week randomized trial comparing methotrexate and auranofin. Arthritis Rheum 1993;36:6139. 2 Emery P, Keystone E, Tony HP et al. 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