Effects of non-surgical periodontal therapy on periodontal clinical data in periodontitis patients with rheumatoid arthritis: a meta-analysis

Backgrounds To date, there is still no consensus about the clinical efficacy of non-surgical periodontal therapy in rheumatoid arthritis (RA) patients with periodontitis. Therefore, the aim of this study was to summarize clinical data regarding the efficacy of scaling and root planing (SRP) in patients with RA and periodontitis compared to non-RA periodontitis patients. Methods We selected randomized controlled trials (RCTs) that compared periodontal clinical data in RA as compared to non-RA periodontitis patients by searching Embase, PubMed and Cochrane Central Register of Controlled Trials and by manually retrieving from the earliest records to March 8, 2021. The overall effect size of plaque index (PI), gingival index (GI), attachment loss (AL), probing depth (PD) and bleeding on probing (BOP) were calculated by either a fixed or random-effect model, and subgroup analyses were conducted according to the different time points of follow-up. Two investigators extracted the data and assess the accuracy of the obtained results with 95% of Confidence Intervals (CI). Cochrane Collaboration's tool was responsible for the evaluation of the literature quality and the inter-study heterogeneity was evaluated by Q test and I2 statistic. Sensitivity analyses were applied for results with heterogeneity. Publication bias was determined by Begg's test, Egger's test and the trim-and-fill method. Results Seven RCTs including 212 patients eventually met the inclusion criteria for the study. As the primary results, the change of PD was not statistically significant and in the secondary results changes of PI, GI, AL and BOP were also not statistically significant in RA patients with periodontitis compared to non-RA periodontitis patients. In subgroup analysis, a larger BOP reduction at 3 months, PI and AL reduction at 6 months were observed in patients with RA and periodontitis group. The results of sensitivity analyses had no significant effect. No evidence of potential publication bias was tested. There were some limitations due to the small number of eligible RCTs. Conclusions SRP is equally effective in RA as compared to non-RA periodontitis patients. It suggests RA does not affect the clinical efficacy of non-surgical periodontal therapy. These results could serve evidence-based practice. Supplementary Information The online version contains supplementary material available at 10.1186/s12903-021-01695-w.


Background
Periodontitis is a chronic in ammation of the periodontal tissues, with negative impact on both local and systemic health. It is well known that the in ammatory state gives rise to a multitude of damage of periodontal tissue, of which the most critical are in alveolar bone, as well as in periodontal ligament [1,2].
In a comprehensive epidemiological report in 1990 and 2010 of severe periodontitis (SP), a global agestandardized rate of severe periodontitis was reported to be high around 11.2% [3]. It suggested a growing global health threat from severe periodontitis. In addition, many modi able and non-modi able risk factors, such as rheumatoid arthritis (RA), diabetes, obesity, high blood pressure, atherosclerosis and other cardiovascular diseases and so on, can modify the individual's risk of developing periodontitis, as well as the response to periodontal therapy [4][5][6][7][8].
RA is a chronic autoimmune disorder and can ultimately lead to the irreversible damage to cartilage in joints and loss of function even, which is closely related to the production of autoantibodies, synovial in ammation and hyperplasia [9,10]. The interplay between RA and periodontitis has long been studied, with evidence showing complex associations between these two distinct diseases [11,12]. The pathogenesis of the two diseases are characterized by local destruction of hard and soft tissues as a consequence of in ammation [13,14]. Additionally, there is strong evidence that people with RA have elevated risk for in ammation of periodontal ligament, respiratory mucosa and intestinal mucosa to some extent [15]. Studies among people with RA demonstrate signi cantly higher prevalence levels in patients with periodontitis [16][17][18]. To date, the mechanisms accounting for the aggravation of periodontitis by RA are not completely clari ed.
The representative of non-surgical periodontal therapy as scaling and root planing (SRP) has been considered as the traditional treatment regime in managing periodontitis. Conventional clinical indices and parameters of periodontal health, namely plaque index (PI), gingival index (GI), attachment loss (AL), probing depth (PD) combined with bleeding on probing (BOP), are usually calculated to determine the e cacy of SRP. In recent years, there have been several works discussing effects of periodontal treatment on RA markers [19][20][21]. Additionally, in a recent meta-analysis, the bidirectional relationship between periodontitis and RA was also analyzed [22]. However, to our knowledge, a comprehensive meta-analysis attempted to establish the clinical e cacy of SRP in periodontitis patients with RA has not yet emerged.
In light of these considerations, meta-analysis is now imperative to assess the difference in the clinical e cacy of SRP between patients with periodontitis and RA and those with periodontitis alone.

Search strategy
In this meta-analysis, we followed the guidelines in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analysis -PRISMA statement [23]. Online Embase, PubMed and Cochrane Central Register of Controlled Trials from the earliest records to December, 2020 were systematically screened for the desired publications. The search keywords included (Rheumatoid arthritis OR RA) AND (periodontitis OR periodontal disease) AND (treatment OR therapy). Additionally, reference lists of related studies and some journals were manually searched for completeness. We didn't place any restrictions on the language of publications when searching these online databases and the unpublished works were not accounted.

Eligibility criteria
The following study designs were included: (1) Type of study design must be randomized controlled trial (RCT); (2) Articles that evaluated the clinical e cacy of SRP in RA patients with periodontitis; (3) SRP was the only treatment; (4) Changes at least in one of the ve clinical periodontal indices/parameters (PI, GI, AL, PD and BOP) were recorded in the study.
The excluded criteria for our study were: (1) The study design was not RCT; (2) Potential participants who had any other disease or combined with systemic antibiotic therapy; (3) Studies lacked of control group; (4) Studies did not record any one of the ve periodontal indices/parameters; (5) Articles where the full text and date was not available.

Data extraction
Two investigators (Z Zhang and Y Huang) screened the titles, abstracts, and full articles independently according to eligibility criteria for study selection. The data extracted from each article including the following data: periodontal indices/parameters included in the results, rst author, year of publication, location, sample size, gender and age, duration of RA, and time point of follow-up. A third researcher addressed all remaining discrepancies after consultation between the two investigators.

Quality assessment
The quality of the RCTs was assessed in accordance with the Cochrane Collaboration's tool, including the following aspects of evaluations: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete of the outcome data; 6.selective reporting and the other bias (i.e. non-objective therapy and completeness of follow up) [24]. Following the Cochrane Collaboration guidelines, each RCT was classi ed as being at low, unclear or high risk of bias.

Statistical analysis
The differences (experimental minus control) of the changes ( nal values minus baseline values) were employed to calculate the net changes between the two groups. The pooled effect was expressed as mean difference (MD) with their associated 95% con dence intervals (CIs). It was de ned as statistically signi cant if p-value was less than 0.05. The Cochran's Q test and I 2 statistic were employed to calculate heterogeneity among the included studies. P < 0.05 (Q test) or I 2 > 50% represented a substantial high level of heterogeneity, in which case the random-effect model was performed [25,26], while the xedeffect model was used when P > 0.05 and I 2 < 50% [27]. Sensitivity analysis was conducted to explore, quantify, and control for sources of heterogeneity and stability of results across studies by excluding eligible studies by sequence. Begg's test [28], Egger's test [29] and the trim-and-ll method [30] were employed to identify the statistical signi cance of publication bias. All above statistical analyses were conducted by Stata (version 12.0, Stata Corp, College Station, TX, USA).

Literature selection
At the beginning, a total of 1,151 records were identi ed from the electronic and manual search, including 509 in PubMed database, 593 in Embase database, 41 in Cochrane Central Register of Controlled Trials and 8 of manual search. After removal of the duplicates, 1048 publications remained for independent screening, of which 1001 were deemed irrelevant on the basis of their title and abstract and 47 publications were eligible for full-text evaluation. Of these articles, 39 were excluded, mostly because of being meta-analysis, case report, review studies (n=9), without full text (n=9), the combination of systemic antibiotic therapy (n=2), being overlapping study (n=1), without available date (n=2) and the lack of control group (n=16). Finally, 8 RCTs met the eligibility criteria in this meta-analysis. (Supplementary gure S1) Characteristics of the included studies As shown in Table 1, main characteristics of the included trials are presented. They were published between 2009 and 2019. There was little variation in the number of participants enrolled in the 8 RCTs (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), reaching a total of 247 with mean age ranging between 41.4 and 51.6 years. The studies were carried out in the following countries: Brazil (n=2), Turkey (n=4), China (n=1) and Germany (n=1). The percentages of female participants in the studies were summarized, which ranged between 40.0% and 100%. All studies reported the percentage of female participants, Five of these studies reported a duration of RA from 6 weeks to 14.9 years and three did not provide the duration information. Length of follow-up period varied amongst the 8 included studies, ranging from 1 to 6 months duration. Seven of the studies included outcomes of PI, PD and BOP, four of AL and three of GI.

Risk of bias within studies
The quality of evidence for each outcome was based on six domains: Selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias. Results were presented graphically by study (Fig. 1A) and proportion chart of bias was set across all studies (Fig. 1B). It is noteworthy that only one of the studies was judged to be at high risk of selection bias, which was observed in Roman-torres 2015. Three studies had an unclear risk of bias in blinding of participants and personnel, 4 studies had an unclear risk of bias in blinding of outcome assessment, and 6 studies had an unclear risk of bias in selective reporting. In addition, with regard to allocation concealment, all studies showed unclear risk.

Meta-analysis of clinical indices
The overall effect size showed that the PI value in periodontitis patients with RA changed more signi cantly compared with periodontitis control patients (MD: 0.42; 95% CI: 0.02, 0.81) ( Fig. 2A).

Sensitivity analysis
Sensitivity analyses were performed in order to assess the potential source of heterogeneity of PI and BOP outcomes. We evaluated the in uence of individual dataset on the pooled effect by sequential removal of each eligible study. However, the ndings were corroboratively robust and no signi cant change was detected for all primary outcomes (Fig.4).

Publication bias
Begg's and Egger's test revealed that there was no publication bias for the changes of PI, GI, AL and BOP (P 0.05), but Egger's test manifested that there was publication bias for PD (Egger's test P=0.04). The trim-and-ll analysis suggested no evidence of signi cant difference between the adjusted value and the original value of PD changes, but revealed a missing study for BOP changes. At the same time, the adjusted value for BOP changes was also not signi cantly different from the original value (Table 2).

Subgroup analysis
To determine the potential in uence of follow-up time on the clinical e cacy of SRP, we performed analyses separately for different follow-up time points. Compared with periodontitis control patients, the reduction of BOP (MD: 5.93; 95%CI: 0.28, 11.58) was signi cantly larger in periodontitis patients with RA at the 3rd month after SRP. Similarly, the changes of PI (MD: 0.60; 95% CI: 0.08, 1.13) and AL (MD: 0.36; 95% CI: 0.06, 065) of periodontitis patients with RA were slightly larger at the 6th month than periodontitis control patients (Table 3).

Discussion
To the best of our knowledge, available evidence was summarized in an effort to speci cally estimate the clinical e cacy of SRP in periodontitis patients with RA for the rst time of meta-analysis. Eight RCTs were included, and all the studies evaluated the changes associated to treatment of the periodontal in ammation, based on the measurement of different clinical indices and parameters (PI, GI, PD, AL and BOP). The ndings from the present meta-analysis failed to nd signi cant difference in the clinical e cacy of SRP between RA patients with periodontitis and patients with periodontitis alone. This provides evidence that RA does not affect the clinical e cacy of SRP in periodontitis.
It has been con rmed that periodontitis patients with RA were found to have higher plaque scores compared to individuals without RA [31]. Our meta-analysis showed that SRP resulted in 0.42 of additional PI reduction in periodontitis patients with RA. SRP appears to be more effective in improving oral hygiene in periodontitis patients with RA than that in patients with periodontitis alone. This nding could be linked to the evidence that a higher prevalence of severe periodontitis in RA patients [32,33]. A further study from Van der Weijden et al indicated that severe periodontitis yielded greater PI reduction after SRP as compared to mild periodontitis [34]. Thus, the results we obtained may be partly attributed to the SRP e cacy for SP rather than the improvement by RA.
Recent report showed that the duration of RA is likely to have a signi cant impact on the association between RA and periodontitis [35]. What's more, Qiao et al declared that periodontitis might be more closely related to disease duration >5 years of RA patients [36]. Also, a signi cantly higher clinical AL was found in moderately-to-highly active RA patients, compared to those in remission [35]. Unfortunately, information about the RA duration was not available in the studies enrolled in our meta-analysis. In addition, we did not con rm a signi cant difference of AL reduction in the two groups. We speculate that an imprecise duration of RA is likely to contribute to no difference in the SRP-related outcomes between groups. Clearly, this needs further investigation in well-designed studies taking this variable into account.
Likewise, several parameters failed to show difference between groups in this meta-analysis. The results showed that the effects of SRP on the GI, PD, BOP of patients with RA and periodontitis were almost consistent with those with periodontitis alone. It is pertinent to mention that previous research demonstrated the application of the mechanical periodontal treatment as SRP could effectively improve periodontal parameters [37]. But whether this effect will change in the presence of RA is unclear. Thus, these ndings con rmed that SRP is an effective treatment for periodontitis and the clinical bene ts of SRP could not be affected by RA in periodontitis patients in this regard.
Cosgarea et al observed a signi cant reduction in some clinical periodontal parameters within 3 and 6 months after treatment in patients with periodontitis and RA [38]. However comparisons of e cacy differences were not achieved. In our study, when strati ed by the points of follow-up, the periodontitis patients with RA showed a higher BOP reduction at 3 months and an overall improvement for PI and AL at 6 months in comparison to periodontitis patients. However, it did not show signi cantly statistical differences in other parameters and follow-up time points. Besides, research reported no difference in clinical parameter outcomes when studying periodontal treatment effects of patients with low and high disease activity of RA [39]. Therefore, the difference in the e cacy of SRP between groups has not been well demonstrated by the outcomes for follow-up within 6 months after treatment.
Although the study was designed seriously and data was processed carefully, we still identi ed several limitations in this meta-analysis. First, the study is likely to lack the statistical power to detect differences between groups due to the limited number of studies and subjects. Second, 3 studies did not publish RA duration. As a result, potential confounding factors could lead to some bias in the outcomes. Third, there may also be some heterogeneity between the two groups in terms of gender and demographic data, which were not analyzed in the subgroup. Finally, some clinical criteria for disease assessing are not entirely consistent and tend to introduce non-differential misclassi cation of the two diseases, with a potential effect of driving the results towards no difference.

Conclusions
Taken together, in spite of these limitations, we conclude that SRP is equally effective in patients with periodontitis and RA than in periodontitis ones. This result suggests RA does not affect the clinical e cacy of non-surgical periodontal therapy. We are looking forward to additional scienti c researches to elucidate the clinical e cacy of SRP in RA patients with periodontitis of various severities further.

List Of Abbreviations
RA, rheumatoid arthritis, SRP, scaling and root planning, RCTs, randomized controlled clinical trials, SP, severe periodontitis, PI, plaque index, GI, gingival index, AL, attachment loss, PD, probing depth, BOP, bleeding on probing, PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses, MD, mean difference, CI, con dence intervals Declarations Ethics approval and consent to participation Not applicable

Consent for publication
Not applicable

Availability of data and materials
The detailed data supporting the study are available upon reasonable request.

Competing interests
All the authors declare no con ict of interest.