Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
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Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit
Does periodontal treatment influence clinical and biochemical measures for rheumatoid arthritis? A systematic review and meta-analysis Sushil Kaur, DClinDenta, Richard Bright, MSca, Susanna M. Proudman, MBBS, FRACP (Rheumatology)b,c, P. Mark Bartold, DDSc, PhDa,n a b c
Department of Dentistry, Colgate Australian Clinical Dental Research Centre, University of Adelaide, South Australia 5005, Australia Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia 5005, Australia Discipline of Medicine, University of Adelaide, Adelaide, South Australia 5005, Australia
a r t i c l e in fo
Keywords: Periodontal diseases Rheumatoid arthritis Inflammation Risk factors
a b s t r a c t Objective: Periodontitis is a potential risk factor for rheumatoid arthritis (RA). This systematic review considers the evidence for whether non-surgical treatment of periodontitis in RA patients has any effect on the clinical markers of RA disease activity. Methods: MEDLINE/PubMed, CINAHL, DOSS, Embase, Scopus, Web of Knowledge, MedNar, Lilacs and ProQuest Theses and Dissertations were searched till September 2013 for quantitative studies examining the effect of non-surgical periodontal treatment on disease activity of RA. The following were the inclusion criteria: (1) patients diagnosed with both RA and chronic periodontitis, aged 30 years or older; (2) no antibiotics in the past 3 months or periodontal treatment in the past 6 months; (3) non-surgical periodontal therapy; (4) age- and gender-matched control group; (5) measures of RA activity and (6) published in English. Results: Five studies met the inclusion criteria. Non-surgical periodontal treatment was associated with significant reductions in erythrocyte sedimentation rate and a trend towards a reduction in TNF-α titres and DAS scores. There was no evidence of an effect on RF, C-reactive protein, anti-cyclic citrullinated protein antibodies and IL-6. Conclusions: Based on clinical and biochemical markers, non-surgical periodontal treatment in individuals with periodontitis and RA could lead to improvements in markers of disease activity in RA. All studies had low subject numbers with the periods of intervention no longer than 6 months. Larger studies are required to explore the effect of non-surgical periodontal treatment on clinical indicators of RA, using more rigorous biochemical and clinical outcome measures as well as giving consideration to potential confounding factors of co-morbidity. Crown Copyright & 2014 Published by Elsevier Inc. All rights reserved.
Introduction There is considerable evidence for a relationship between the chronic inflammatory diseases, rheumatoid arthritis (RA) and periodontitis [1]. RA is characterised by clinical and pathologic processes similar to the soft and hard tissue destruction seen in chronic periodontitis [2]. Periodontitis is a chronic oral inflammatory
The National Health and Medical Research Council of Australia has provided funds to support research staff and laboratory expenses. This study was funded in part by National Health and Medical Research Council of Australia (Grant no. 1023747). n Corresponding author. E-mail address:
[email protected] (P.M. Bartold). http://dx.doi.org/10.1016/j.semarthrit.2014.04.009 0049-0172/Crown Copyright & 2014 Published by Elsevier Inc. All rights reserved.
disease of the supporting structures of the teeth (root cementum, periodontal ligament and alveolar bone) and, if left untreated, leads to tooth loss [3]. An imbalance between pro-inflammatory and antiinflammatory cytokines, thought to be responsible for the tissue damage, is evident in both RA and periodontitis. Both conditions are associated with bone destruction, mediated by inflammatory cytokines such as interleukin 1, tumour necrosis factor-alpha (TNF-α) and prostaglandin E2 [4,5]. There is significant evidence that other systemic conditions are linked to periodontitis, such as cardiovascular disease, type 2 diabetes mellitus, osteoporosis and adverse pregnancy outcomes [6]. More recently, systematic reviews and meta-analyses have shown that periodontal treatment improves endothelial function and reduces biomarkers of arteriosclerotic disease [7,8].
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Several hypotheses have been proposed for the relationship between RA and periodontitis. Of these, two in particular, are promising. One is referred to as the “two-hit” model, in which a primary “hit” of chronic inflammation via chronic periodontitis followed by a secondary arthritogenic hit to induce RA can lead to an exacerbated inflammatory response [9]. The second hypothesis proposes that autoimmune responses develop to proteins that are partially altered by either the host inflammatory process or bacterial enzymes [10]. One example is the appearance of anticitrullinated protein autoantibodies (ACPA) during the development of RA. Given that similar dysregulation of host inflammatory processes occurs in the pathogenesis of both diseases, it has been proposed that both conditions could influence each other in a bidirectional manner. Accordingly, it has been proposed that reducing the systemic burden of inflammation, such as that due to periodontitis, may have beneficial effects on the clinical activity of RA. Disease activity of RA can be measured by laboratory tests as well as clinical evaluation (patient-reported outcomes of pain, global assessment and fatigue and physical examination). The Disease Activity Score (DAS28) involves the assessment of tenderness and swelling in 28 joints that are most frequently affected in RA along with an acute-phase reactant, either erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) and the patient's global assessment of overall health status as assessed on a 100-mm visual analogue scale [11]. Laboratory tests that may change in response to disease activity include acute-phase reactants such as ESR, CRP, ACPA, rheumatoid factor (RF), tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and interleukin-6 (IL-6). A recent systematic review identified three studies that investigated the effect of periodontal treatment on biochemical markers of RA disease activity [1]. It was concluded that the results of these studies provide emerging evidence for a correlation between nonsurgical periodontal treatment and improved outcomes for RA patients. More recently, additional reports have been published investigating the effect of periodontal treatment on clinical markers of disease activity for RA. Therefore, the objective of this systematic review was to assess whether periodontal treatment could improve biochemical and clinical measures in patients suffering from RA.
Methods Search strategy The search strategy aimed to find both published and unpublished studies in the English language from inception of the database until September 2013. A three-step search strategy was utilised in this review. An initial limited search of MEDLINE was followed by analysis of the text words contained in the title and abstract and of the index terms used to describe the article. The databases used for secondary searches for published studies were Medline/PubMed, DOSS, Embase, Lilacs and Scopus. The search for unpublished studies included Web of Knowledge, MedNar and ProQuest Theses and Dissertations. Initial keywords/search terms used were rheumatoid arthritis, periodontal disease, biochemical markers and periodontal treatment. The subsequent specific search strategies are detailed in Appendix I. Inclusion criteria Following retrieval of all relevant articles, the titles and abstracts were screened (SK). Only articles with full text were
considered further. To be included, the studies had to meet the following criteria: (1) quantitative studies that examined the effect of periodontal treatment of chronic periodontitis in patients diagnosed with both RA and chronic periodontitis; (2) patients diagnosed with both RA and chronic periodontitis, aged 30 years or older; (3) no antibiotic usage in the previous 3 months, no systemic conditions likely to affect either RA or chronic periodontitis and no periodontal treatment in the previous 6 months; (4) periodontal intervention was to be non-surgical without the use of any adjunctive agents such as antibiotics or host-modulating medications; (5) control group of age- and gender-matched individuals receiving no periodontal treatment for the duration of the study or baseline measure; (6) outcome measures of RA activity to include CRP, ESR, ACPA, TNF-α, RF, IL-1β, IL-6 and DAS28 and (7) published in English. Diagnosis of periodontal disease was based on the clinical and radiographic criteria described by the 1999 Consensus Classification of Periodontal Diseases [12] while diagnosis of RA was based on criteria of the American College of Rheumatology [13]. Data were extracted by all reviewers (S.K., R.B. and P.M.B.) detailing the following information: patient characteristics (age, gender, periodontal diagnosis and smoking status) and type of intervention undertaken.
Assessment of methodological quality Articles were independently selected for retrieval and assessed for methodological validity by three reviewers (S.K., R.B. and P.M.B.) using standardised critical appraisal instruments from the Joanna Briggs Institute Meta-analysis of Statistics Assessment and Review Instrument (JBI-MAStARI, Joanna Briggs Institute, University of Adelaide) (Appendix II). Disagreements that arose between the reviewers were resolved through discussion.
Data collection Quantitative data were extracted from the articles using the standardised data extraction tool from JBI-MAStARI. This process extracted specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives (Appendix III). Attempts were made to contact original authors if we required additional or missing data and to identify further references. No additional data or information was obtained from such attempts.
Data synthesis Quantitative articles were, where possible, pooled in statistical meta-analysis using MedCalc Statistical Software version 12.7.4 (MedCalc Software bvba, Ostend, Belgium; http://www. medcalc.org; 2013). To assess overall efficacy from all the studies included in the meta-analysis, we calculated pooled standardised mean difference (SMD) using both random-effects and fixed-effects models, reporting heterogeneity and overall p-values. An I2 4 50% indicated high heterogeneity between studies; thus, the random-effect model would be adopted. To calculate SMD from studies that did not report standard deviation, inter-quartile ranges or ranges were transformed to standard deviation assuming a normal distribution curve. We calculated effect sizes for each study and overall pooled effect sizes with 95% CI [14]. Statistical significance was declared if the p value was less than 0.05.
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Results Description of studies The search identified 1099 studies after duplicates were removed. Based on assessment of the title and abstract, 48 studies were retrieved for examination. Of these 48 full-text articles retrieved, five met the inclusion criteria and were included in the review. Figure 1 summarises the study identification process. There was no disagreement concerning the selection of the final five articles included in the review. The five articles included in this review were all original research articles and were all single-centre intervention studies [15–19]. They included studies published up to June 2013 and were conducted across broad geographical locations (Brazil, Japan, USA and Turkey), representing studies on participants from different ethnic and cultural backgrounds. Participants in the included studies had a confirmed diagnosis of RA together with mild to severe periodontitis at baseline. The studies ranged from 6-week [17], 8-week, [15,16] 3-month [19] to 6-month [17] evaluation periods. A summary of the study designs, clinical and laboratory
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data, findings and outcomes of each included article can be found in Table 1. A list of the studies excluded from this review and the reasons for these decisions are shown in Appendix IV. The outcome of interest to this review was the influence of non-surgical periodontal treatment on clinical and biochemical measures for RA disease activity. The measures of RA disease activity in the studies included DAS28, ESR, CRP, ACPA, RF, TNF-α, IL-1 and IL-6. Rheumatological outcomes following non-surgical periodontal treatment of RA and periodontal disease Five studies that examined the effect of non-surgical periodontal treatment on clinical and biochemical markers for RA disease activity were included [15–19]. Measures of RA disease activity following non-surgical periodontal treatment covered a wide range of markers and were not used uniformly across the studies. All studies generally controlled for other co-morbidities (apart from periodontitis) albeit in a non-uniform manner. Subject sample sizes varied from 10 to 26 in the treatment (intervention) groups and from 10 to 29 in the control groups. The duration of the
Records identified through database searching (n=1059)
Additional records identified through other sources (n=117)
Records after duplicates removed (n=1099)
Records excluded (n=548) - Book chapter - Title - Abstract
Records screened (n=551)
Full-text articles assessed for eligibility (n=48)
Records excluded (n=503) -
Basic science Non-quantitative Review Incorrect measures
Full-text articles excluded (n=36) Full-text assessed in detail (n=12)
Studies included in this systematic review and meta-analysis (n=5)
Final exclusion of articles (n=7)
Exclusion (qualitative) Ribeiro 2005 (n=1)
Studies included in metaanalysis (n=4) DAS (n=3), ESR (n=3), CRP (n=2) & TNF (n=2) Fig. 1. PRISMA flow diagram for studies retrieved through the searching and selection process.
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Table 1 Table of Included studies. Studies assessing the effects of intervention in subjects with RA and/or periodontitis References Study conditions
Patient demographics
Treatment outcome
Author conclusions
DAS-CRP (p o 0.02), citrulline (p o Results suggest that supraDAS28-CRP, patient's gingival scaling decreases 0.04), anti-P.gingivalis (p o 0.04), general assessment DAS28-CRP and serum levels PPD and CAL reduced significantly VAS, ESR, anti-CCP, RF, of IgG to P. gingivalis and (p o 0.001) TNF-α and anti-P. citrulline in RA patients gingivalis GI, PD and CAL
DAS28, patient's general VAS and DAS28 in the treatment group showed improvement assessment VAS and ESR CAL, PD, BOP and GI PPD
DAS28, CRP, ESR and α-1 acid glycoprotein (AAG) PPD, GI and PI
ESR not significant
Non-surgical periodontal therapy had a beneficial effect on the signs and symptoms of RA regardless of medications being taken
PPD and CAL had improvement in treatment group with RA. Serum TNF-α levels improved after treatment (p o 0.001) RA, PD and TX: PPD reduced (p o The relationship between RA 0.01), acute-phase laboratory data; and periodontitis activity AAG, ESR and CRP not significant unclear
DAS28, patient's general Overall, 58.8% (VAS), 76.4% (DAS28) and 76.4% (ESR) in the treatment assessment VAS and group showed improvement. PPD ESR and CAL improved in treatment PI, GI, PPD and CAL group with RA
Control of periodontal infection and inflammation by nonsurgical treatment subjects with periodontal disease may reduce the severity of RA
HAQ, RF and ESR
Data suggest that periodontal treatment with scaling and root planing might have an effect on ESR reduction
PI, GI, PPD and CAL
RF significantly reduced following scaling and root planing. PPD improved in both groups but CAL only at advanced sites in group with subgingival debridement
AAP, American Academy of Periodontology; ARA, American Rheumatology Association; ACR, American College of Rheumatology; PD, periodontitis; BOP, bleeding on probing; PPD, probing pocket depth; CAL, clinical attachment level; RF, rheumatoid factor; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HAQ, health assessment questionnaire; DAS28, Disease Activity Score; VAS (patient's general assessment), visual analogue scale.
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Control: age, 62.7 7 2.3 years; 82.8% were female. Single-centre intervention over 8 weeks. A total of 26 Treatment: age, 60.7 7 2.7 years; 84.6% were subjects received oral hygiene instructions and suprafemale, 55 adults with RA confirmed to fulfil the gingival cleaning. A total of 29 subjects (control group) 1987 classification Criteria of American received no periodontal treatment. RA defined by the Rheumatism Association and confirmed to exhibit ARA/ACR criteria. Periodontal condition determined by GI, mild to moderate chronic periodontitis, according PD and CAL. Assess serum IgG antibodies to P.gingivalis to the classification of the American Academy of and citrulline with effects of non-surgical periodontal Periodontology. No antibiotic treatment within therapy in RA subjects with periodontitis. the previous 3 months, all subjects took DMARDs or NSAIDS. No mention of medication change during study. Ortiz et al. Single-centre intervention study in over 8 weeks. Groups A Group A: age, 69 years; 80% were female. Group B: [17] and B: 20 subjects taking DMARDs. age, 49; 100% were female. Group C: age, 54 years; 80% were female. Group D age, 63 years; 90% were female. Groups C and D: 20 taking DMARDs and anti-TNF A total of 40 participants diagnosed with moderate/ medication. Groups B and D: 10 subjects received nonsevere RA, under treatment for RA and severe surgical periodontal treatment. Groups A and C: 10 in each periodontitis. No antibiotic use during the group did not receive any periodontal treatment. RA 3 months prior to the study, no smoking. A total of unspecified but appears to have been according to the ACR 20 subjects were taking DMARDs and anti-TNF-α. No changes in medication during the study were criteria. Periodontal condition determined not specified discussed. but is stated to be generalised severe chronic periodontitis. Assess effects of non-surgical periodontal therapy on serum TNF-α in RA subjects with periodontitis. Average age, 50 years. Single-centre intervention study in over 6 months. Five Pinho et al. groups of 15 subjects. Group 1: RA þ PD þ non-surgical [18] treatment, Group 2: RA þ PD þ no treatment, Group 3: RA þ prosthesis þ treatment, Group 4: PD but no RA þ Overall, 60% groups were female. treatment and Group 5: no PD or RA and no treatment. RA The medication used by the patients was maintained to avoid study interferences. No defined by the ACR criteria [13]. Periodontal condition antibiotics within the previous 3 months and no determined according to Machtei et al. [44]and based on smoking. PPD and CAL. Al-Katma Pilot clinical trial, single-centred over 8 weeks. A total of 17 Control: 51.7 7 12.3; 83.0% were female. subjects received periodontal treatment and 12 received et al. no treatment. RA defined by the ACR criteria. Periodontal [15] condition determined according to the AAP criteria with Treatment: age, 55.0 7 9.4 years; 88.0% were periodontitis. female. A total of 29 subjects with confirmed diagnosis of RA and mild to moderate chronic periodontitis of at least 3 years duration. No antibiotic use during the previous 300 days before the study and no changes in medication during study. Control: 47.7 7 9.5; 93.0% were female. Single-centre intervention study in 42 subjects over Ribeiro 3 months. A total of 16 subjects received oral hygiene et al. instructions and supra-gingival cleaning. A total of 16 [19] subjects received full-mouth debridement. RA defined by the ARA criteria. Treatment: age, 51.6 7 10.3 years; 88.5% were female. A total of 42 patients with confirmed RA had at least Z2 teeth and at least Z 2 sites with pocket depths Z 5 mm and attachment level Z 6 mm at baseline.
Okada et al. [16]
Outcome measures
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intervention varied from 8 weeks to 6 months. Data were analysed using a variety of statistical software packages and processes with non-parametric tests with p-values set at o0.05 for statistical significance. Biochemical markers in rheumatoid arthritis patients with periodontal disease Disease activity score (DAS28) Four studies reported disease activity scores in patients with RA and periodontitis [13,15,17,19] (Table 2). One of the studies [15] measured DAS28 using CRP as the acute-phase reactant and three of the studies measured DAS28 using ESR [13,17,19]. Previously, it has been shown that DAS28 ESR and DAS28-CRP correlate well [20]. All four studies showed a reduction in DAS scores following non-surgical periodontal treatment. Only three of the studies could be included in the meta-analysis because one of the studies did not provide standard deviation information [19]. When the remaining three studies were combined in meta-analysis, the overall SMD between the treatment and the non-treatment groups was 1.217 (95% CI: 2.632 to 0.198). While not statistically significant, this result indicates a trend towards a reduction in DAS28 scores following conservative non-surgical periodontal treatment (Fig. 2).
Erythrocyte sedimentation rate (ESR) ESR is a good surrogate marker for the presence of systemic inflammation and is useful for determining disease activity in RA [21]. Four studies measured ESR by the Westergren method [22] following non-surgical periodontal treatment of patients with both RA and periodontitis [15,17–19] (Table 2). Frequency distributions, means and standard deviation were determined to describe the data. Three of the studies reported a decrease in ESR levels following non-surgical periodontal treatment in RA patients. Of the three studies, two [15,19] showed a significant decrease in ESR values in the RA patients following periodontal treatment (p o 0.05). Only three of the studies could be included in the meta-analysis because one of the studies did not provide standard deviation information [19]. When the remaining three studies were combined in meta-analysis, the overall SMD difference between the treatment and the non-treatment groups was 0.479 (95% CI: 0.924 to 0.034). This suggests that ESR is
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significantly reduced in RA patients following non-surgical periodontal treatment (Fig. 3). C-reactive protein (CRP) CRP, which is synthesised in the liver, is an acute-phase protein. Like ESR, CRP is a surrogate marker for systemic inflammation and is useful for determining disease activity in RA [21]. Two studies reported serum CRP levels analysed immunologically with a commercial kit following non-surgical periodontal treatment of patients with both RA and periodontitis [16,18] (Table 2). Frequency distributions, means and standard deviation were determined to describe the data. There was no statistically significant decrease in CRP levels in RA patients undergoing non-surgical periodontal treatment compared to the control group. These findings were confirmed when combined in meta-analysis, in which the overall SMD between the treatment and the nontreatment groups was 0.072 (95% CI: 0.497 to 0.352), indicating that CRP is not significantly reduced in RA patients following non-surgical periodontal treatment (Fig. 4). Tumour necrosis factor-α (TNF-α) The pro-inflammatory cytokine, TNF-α, is prevalent in many chronic inflammatory disorders, including RA and periodontitis. Anti-TNF antibodies are used as a biological therapy to regulate the effects of this cytokine in RA [23]. Two studies were identified that reported TNF-α levels following non-surgical periodontal treatment of patients with both RA and periodontitis [16,17] (Table 2). TNF-α was analysed using Luminex human cytokine/chemokine multiplex kits. Of the two studies, one reported a statistically significant decrease in TNF-α levels following non-surgical periodontal treatment in RA patients (p o 0.001) [17]. However, when combined in a meta-analysis, the overall SMD between the treatment and the non-treatment groups was 1.352 (95% CI: 3.072 to 0.369), thus indicating there was a trend for a reduction in TNF-α but not significantly (Fig. 5). Rheumatoid factor (RF) RF has been used for many years as a diagnostic aid for RA; however, it is not a very specific marker since up to 15% of rheumatoid patients are seronegative for RF [24]. RF has also been reported to be present in periodontitis subjects [25]. Two studies were identified that reported RF analysed by ELISA following non-surgical periodontal treatment of patients with both RA and periodontitis [16,19] (Table 2).
Table 2 Effect of non-surgical periodontal treatment on rheumatoid arthritis biomarkers in rheumatoid arthritis patients (mean 7 SD) Biomarker
References
RA þ periodontal treatment
RA no periodontal treatment
Statistical association
DAS
Okada et al. [16] Ortiz et al. [17] Al-Katma et al. [15] Ribeiro et al. [19]
2.06 7 0.15, n ¼ 26 3.51 7 1.11, n ¼ 10 4.3 7 1.6, n ¼ 17 53.8 (no SD provided), n ¼ 26
2.44 7 0.14, n ¼ 29 3.98 7 0.63, n ¼ 10 5.1 7 1.2, n ¼ 12 75 (no SD provided), n ¼ 16
p p p p
¼ 0.02 ¼ 0.005 o 0.05 o 0.05
Intervention Intervention Intervention Intervention
ESR
Ortiz et al. [17] Pinho et al. [18] Al-Katma et al. [15] Ribeiro et al. [19]
10.5 7 8, n ¼ 10 22.40 7 13.13, n ¼ 15 31.4 7 20.4, n ¼ 17 53.8 (no SD provided), n ¼ 26
10.50 7 15, n ¼ 10 28.33 7 8.47, n ¼ 15 42.7 7 22, n ¼ 12 75 (no SD provided), n ¼ 16
p p p p
¼ 0.64 ¼ 0.16 o 0.05 o 0.05
Intervention Intervention Intervention Intervention
CRP
Okada et al. [16] Pinho et al. [18]
0.39 7 0.12 n ¼ 26 0.63 7 0.54, n ¼ 15
0.39 7 0.08 n ¼ 29 0.81 7 1.10, n ¼ 15
p ¼ 0.86 p ¼ 0.29
Intervention Intervention
Anti-CCP TNF-α
Okada et al. [16] Okada et al. [16] Ortiz et al. [17]
197.2 7 24.1, n ¼ 26 0.82 7 0.18, n ¼ 26 42.48 7 42.49, n ¼ 10
219.93 7 25.6, n ¼ 29 1.86 7 0.62, n ¼ 29 77.89 7 93.59, n ¼ 10
p ¼ 0.21 p 4 0.05 p o 0.001
Intervention Intervention Intervention
RF
Okada et al. [16] Ribeiro et al. [19]
66.4 7 16.0, n ¼ 26 8.7 (no SD provided), n ¼ 26
105.3 7 29.1, n ¼ 29 0 (No SD provided), n ¼ 16
p ¼ 0.84 No significance
Intervention Intervention
IL-6
Okada et al. [16]
5.62 7 1.14 n ¼ 26
5.97 7 1.12 n ¼ 29
p ¼ 0.14
Intervention
Study design
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DAS
Okada et al 2013 Ortiz et al 2009 Al-Katma et al 2007
Total (fixed effects) Total (random effects) -4
-3
-2
-1
0
1
SMD
Study Okada et al. 2013 Ortiz et al. 2009 Al-Katma et al. 2007 Total (fixed effects) Total (random effects)
Treatment 26 10 17 53 53
Control 29 10 12 51 51
Total 55 20 29 104 104
SMD -2.587 -0.499 -0.536 -1.303 -1.217
SE 0.363 0.435 0.373 0.223 0.713
95% CI -3.315 to -1.859 -1.414 to 0.416 -1.302 to 0.230 -1.746 to -0.860 -2.632 to 0.198
Test for heterogeneity Q DF Significance level I2 (inconsistency) .’95% CI for I2
20.150 2 P < 0.0001 90.07 % 73.53 to 96.28
Fig. 2. Forest Plots of SMD between treatment and non-treatment groups for (A) DAS.
Neither of the studies demonstrated a statistically significant change in RF levels following non-surgical periodontal treatment in RA patients with periodontal disease. However, because the study published by Ribeiro et al. [19] did not include standard deviation data, no meta-analysis could be performed for RF. Anti-citrullinated protein antibodies (ACPA) Inflammation can result in local citrullination of proteins and subsequent production of ACPA. The presence of ACPA in the serum is quite specific for RA and is useful diagnostically. The specificity in established RA may be as high as 95%, however, between 40% and 55% in early-onset RA [26,27]. The levels can fluctuate with disease activity [24]. Recently, citrullinated proteins and ACPA have been identified in inflamed periodontal tissues [28,29] and non-surgical periodontal treatment can lead to a reduction of ACPA in periodontitis patients [30]. In this systematic review, only one study reported the levels of ACPA, measured by enzyme-linked immunosorbent assay (ELISA) with a commercially available kit, following non-surgical periodontal treatment of patients with both RA and periodontitis [16] (Table 2). There was no statistically significant difference in ACPA titres in patients with RA treated with nonsurgical periodontal treatment compared with those in the control groups (p ¼ 0.21). No meta-analysis was possible for ACPA. Interleukin-6 (IL-6) IL-6 is also elevated in patients suffering from both RA and periodontitis. As for TNF-α, anti-IL-6 antibodies are used as a
biological therapy in the management of RA [31]. A study reported IL-6 levels, measured using commercial ELISA kits following nonsurgical periodontal treatment of patients with RA and periodontitis [16] (Table 2). In this study, a decrease in IL-6 levels was reported in subjects who received non-surgical periodontal treatment; however, it was not significant (p ¼ 0.14). No meta-analysis was possible for IL-6.
Discussion For this review, 12 articles were identified investigating the effect of non-surgical periodontal treatment on clinical and biochemical markers of RA disease activity. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Using the critical appraisal instrument, five articles met the inclusion criteria to allow an assessment of the effect of periodontal treatment on disease activity measures of RA. However, all studies included in this review had low subject numbers, and one of the five studies did not mention randomisation of the participants [19]. In all of the selected studies, the participants had mild to advanced periodontitis as generally assessed by the American Academy of Periodontology classification system [12]. In all of the studies, conservative non-surgical periodontal treatment consisting of oral hygiene instruction and subgingival debridement over multiple visits was carried out; and in all cases, this led to an improvement in periodontal clinical
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ESR
Ortiz et al 2009 Pinho et al 2009 Al-Katma et al 2007
Total (fixed effects) Total (random effects) -1.5 -1.0 -0.5
0.0
0.5
1.0
SMD
Study Ortiz et al. 2009 Pinho et al. 2009 Al-Katma et al. 2007 Total (fixed effects) Total (random effects)
Treatment 10 15 17 42 42
Control 10 15 12 37 37
Total 20 30 29 79 79
SMD 0.000 -0.621 -0.699 -0.479 -0.479
SE 0.428 0.364 0.378 0.224 0.224
95% CI -0.900 to 0.900 -1.367 to 0.125 -1.474 to 0.077 -0.924 to -0.034 -0.924 to -0.034
Test for heterogeneity Q DF Significance level I2 (inconsistency) 95% CI for I2
1.740 2 P = 0.4189 0.00 % 0.00 to 96.14
Fig. 3. Forest Plots of SMD between treatment and non-treatment groups for ESR.
parameters. The study observation periods ranged from 6 weeks to 6 months, which is considered to be of short duration but are of sufficient length to observe clinical changes in terms of reduction in inflammation, infection and probing depth [32]. Of the six clinical and laboratory outcome measures for RA disease activity, the following were included for meta-analysis: DAS scores (n ¼ 5), ESR (n ¼ 4), CRP (n ¼ 3), TNF-α (n ¼ 2) and RF (n ¼ 2). Only a single study reported for ACPA, RF and IL-6, and therefore, metaanalyses for these markers were not possible [19]. In recent years, there has been increasing evidence that periodontitis and RA may be interrelated diseases [1]. However, as for any of the systemic conditions associated with periodontal disease, this relationship could simply be due to another factor(s) that influences both conditions. Whether there is a causeand-effect relationship between RA and periodontitis cannot be determined from such studies. Nonetheless, recent studies in experimental animals have provided interesting insights into the potential for periodontitis to influence experimental arthritis and vice versa [33,34]. In light of these findings, it is now important to determine whether the treatment of one condition (periodontitis or RA) has the potential to influence the clinical outcome of the other. For example, does treatment of periodontal disease in patients suffering from RA have any effect on the disease activity of RA? To determine whether this is a useful area for further research, we undertook this systematic review of the outcomes of the first such intervention studies published to date.
The limited number of studies considered in this review generally had low participant rates and the effects of the intervention were observed over a relatively short period of time (up to 6 months). Measures of RA disease activity were relatively consistent across the studies but did not always include all the clinical and biochemical markers selected by the reviewers for assessment. In all studies, co-morbidities (apart from periodontitis) were generally controlled. Thus, at best, these studies can be considered very preliminary and indicate the need for further large-scale intervention studies using more rigorous clinical and biochemical measures as well as giving consideration to potential confounding factors of co-morbidity to determine whether non-surgical periodontal treatment can indeed influence RA disease experience. In this systematic review and meta-analysis, ESR was significantly reduced, suggesting a reduction in systemic inflammation after non-surgical periodontal treatment in patients with RA. In addition, while not statistically significant, TNF-α titres and DAS scores showed a trend towards a decrease following non-surgical periodontal treatment. Unexpectedly, there was little evidence that non-surgical periodontal treatment can influence CRP levels in RA patients with periodontal disease [16,18]. This is in contrast to other studies that have demonstrated clear reductions in CRP levels in non-RA periodontitis patients following non-surgical periodontal treatment [35–37]. This lack of effect in RA subjects may be due to the small sample size used in the studies or the masking of effect due to the use of disease-modifying
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CRP
Okada et al 2013 Pinho et al 2009
Total (fixed effects) Total (random effects)
-1.0
Study Okada et al. 2013 Pinho et al. 2009 Total (fixed effects) Total (random effects)
-0.5
Treatment 26 15 41 41
0.0 SMD
0.5
Control 29 15 44 44
1.0
Total 55 30 85 85
SMD 0.000 -0.202 -0.0724 -0.0724
SE 0.266 0.356 0.213 0.213
95% CI -0.534 to 0.534 -0.932 to 0.528 -0.497 to 0.352 -0.497 to 0.352
Test for heterogeneity Q DF Significance level I2 (inconsistency) 95% CI for I2
0.206 1 P = 0.649 0.00 % 0.00 to 0.00
Fig. 4. Forest Plots of SMD between treatment and non-treatment groups for CRP.
anti-rheumatic drugs, leading to a low RA disease activity state [38]. Clearly, this needs further investigation in well-designed and controlled intervention studies taking these variables into account. Other biomarkers for RA include ACPA and RF [39]. In the present study, we found no evidence that non-surgical periodontal treatment can influence ACPA titres or RF titres in patients with RA undergoing non-surgical periodontal treatment. This could be explained by the small numbers of patients and the even smaller number of seropositive patients included in the studies as not all patients are positive for one or more of these antibodies. Antibody titres do not always reflect disease activity and are less responsive to the effects of disease suppression. The relationship between ACPA, periodontal treatment and RA is of particular interest since peptidyl arginine deiminase-1 and -2, the enzyme responsible for citrullinating proteins, and citrullinated proteins have been demonstrated within inflamed periodontal tissues [28,29]. Since ACPA appear early in the pathogenesis of RA [39,40], it is now important to determine whether a reduction in periodontal inflammation could reduce ACPA levels and define what, if any, effect this may have on RA disease activity and outcomes. Lipopolysaccharides from bacteria associated with periodontal disease can stimulate the production of RF [25,41,42]. Hence, locally produced RF could amplify inflammatory responses and contribute to the pathogenesis of RA [43], although production of RF could simply be an epiphenomenon to the immune responses of RA without any direct pathogenic effect. As for ACPA, it will be
important in larger scale studies to determine whether modulation of RF production in the periodontal tissues has any bearing on RA outcome measures. Inflammatory cytokines have a well-established role in the pathogenesis of both RA and periodontitis. Initially, we wanted to investigate IL-1, IL-6 and TNF-α since these cytokines are closely associated with both periodontitis and RA disease activity. Furthermore, medications that specifically target these inflammatory cytokines reduce RA disease activity. However, studies to date have not investigated IL-1 and only IL-6 and TNF-α have been considered. This review found some evidence for a reduction in both IL-6 and TNF-α following non-surgical periodontal treatment in RA subjects; however, there have only been limited interventional studies to date, so no meta-analysis was possible for IL-6.
Conclusion This systematic review and meta-analysis has considered the currently available evidence regarding the possible effect of nonsurgical periodontal treatment on RA disease activity. All of these studies had appropriate control groups but suffered from low sample sizes and short study duration. Some studies were difficult to merge or compare results (i.e., data not reported or no control), so definitive conclusions could not be drawn. Nonetheless, this review and meta-analysis provides support for the hypothesis that control of periodontal infection and gingival inflammation by nonsurgical periodontal treatment could reduce the clinical and
S. Kaur et al. / Seminars in Arthritis and Rheumatism ] (2014) ]]]–]]]
9
TNF-α
Okada et al 2013 Ortiz et al 2009
Total (fixed effects) Total (random effects)
-4
Study Okada et al. 2013 Ortiz et al. 2009 Total (fixed effects) Total (random effects)
-3
-2 -1 SMD
Treatment 26 10 36 36
0
Control 29 10 39 39
1
Total 55 20 75 75
SMD -2.194 -0.467 -1.541 -1.352
SE 0.339 0.435 0.267 0.863
95% CI -2.873 to -1.515 -1.380 to 0.446 -2.074 to -1.009 -3.072 to 0.369
Test for heterogeneity Q DF Significance level I2 (inconsistency) 95% CI for I2
9.831 1 P = 0.002 89.83 % 62.51 to 97.24
Fig. 5. Forest Plots of SMD between treatment and non-treatment groups for TNF-α.
biochemical markers of active RA. Larger studies with well-defined primary outcomes and duration of at least 12 months are required to fully determine whether periodontal treatment has any effect on RA disease activity.
Acknowledgements The authors would like to acknowledge the support of Michael Draper, Research Librarian, and University of Adelaide.
Appendix. Supplementary information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.semarthrit.2014. 04.009.
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