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RESEARCH REPORTS |
Department of Periodontology and Eastman Clinical Investigation Center, Eastman Dental Institute and Hospital, University College London, 256 Gray’s Inn Road, London WC1X 8LD, UK;
* corresponding author, m.tonetti{at}uchc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: periodontitis • inflammation • atherosclerosis • cholesterol • C-reactive protein
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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Chronic low-grade inflammation, measured as elevated C-reactive protein (CRP) serum levels, has been directly associated with the onset and progression of cardiovascular diseases (CVD) (Libby et al., 2002; Pearson et al., 2003). CRP hepatic production is usually elicited by an inflammatory stimulus and mediated through a complex network of cytokines (mainly IL-6); nonetheless, several systemic co-factors can influence its concentration (Kluft and de Maat, 2001). It is still unclear, however, whether its predictive role has etiologic implications, or whether elevated CRP concentrations are only a marker of atherosclerosis and/or vascular damage. Epidemiological evidence that other inflammatory markers share the same predictive value of CRP gives strength to the significance of systemic inflammation, rather than one specific marker, on the atherosclerotic process (Pradhan et al., 2002).
In a preliminary intervention study, we showed how standard dental treatment led to a reduction in serum CRP and IL-6 associated with the level of dental clinical response, as determined by periodontal parameters (D’Aiuto et al., 2004). This suggested a potential dose-response effect between the extent of resolution of the local periodontal infection and the level of reduction in systemic inflammation. However, the limitations of the design (uncontrolled) adopted did not allow for proper interpretation of the results, which might have been confounded by changes in other factors (body weight, smoking, medications).
Analysis of recent data has also shown that the improved control of periodontitis achieved with local delivery of antibiotics leads to adjunctive systemic benefits (Iwamoto et al., 2003).
The specific aim of this three-arm, single-blind, randomized, controlled intervention trial was to test the short-term effects of two regimens of periodontal therapy on the systemic inflammatory status of medically healthy individuals suffering from severe, generalized periodontitis. Changes in serum CRP levels were selected as the primary outcome variable, with changes in serum IL-6 and cholesterol levels being chosen as secondary outcomes.
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MATERIALS & METHODS |
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At a baseline visit, a blind examiner collected a complete medical history, standard clinical periodontal parameters, and blood samples. Using a random permuted block approach, stratified based on smoking status (current vs. non-smoker), the trial coordinator randomized subjects to 1 of the 3 treatments groups (Pocock, 1979). A total of 70 individuals met the inclusion criteria. Sixty-five subjects were enrolled and randomized to treatment; the remaining five subjects did not consent. Allocation was concealed by the use of opaque envelopes, which were opened by the therapist at the treatment visit. The 3 groups consisted of: an untreated control (24 subjects); a standard regimen of periodontal therapy (SPT, 21 subjects), consisting of subgingival mechanical instrumentation; and an intensive course of periodontal treatment (IPT, 20 subjects), consisting of SPT with adjunctive local delivery of minocycline-HCl (Arestin®, Orapharma, Warminster, PA, USA). Periodontal and inflammatory outcomes were re-assessed 2 mos following completion of periodontal therapy. All 65 individuals reached this follow-up visit.
Inflammatory Markers and Blood Lipid Measurements
Serum samples were immediately stored at –70°C and processed blind by staff at the end of the trial for CRP levels (Immunoturbidimetric assay, Cobas Integra, Roche AG Diagnostics, Mannheim, Germany; detection limit, 0.25 mg/L) and IL-6 (Quantikine HS, R&D System, Minneapolis, MN, USA; detection limit, 0.04 ng/L). Total and LDL-cholesterol levels were determined by standard clinical chemistry procedures (Hitachi 917, Roche AG Diagnostics, Mannheim, Germany).
Statistical Methods
Based on our previous investigation, 20 patients per treatment arm provided 80% power to detect a difference of 0.4 mg/L in CRP concentrations, with alpha set at 0.05 (D’Aiuto et al., 2004). We used an intention-to-treat analysis. Continuous, normally distributed variables are reported as mean ± standard deviation (SD) and 95% confidence intervals (95% CI). Comparisons of continuous and categorical data between groups at baseline were analyzed with ANOVA and the chi-square test, respectively. Changes in serum concentrations of CRP were tested by one-way analysis of covariance as primary outcomes, and Bonferroni multiple comparisons were performed between treatment groups. Age, gender, ethnicity, body mass index, and cigarette smoking status were subsequently included as covariates in a second model. Changes in IL-6, total/LDL/HDL cholesterol, and triglycerides were tested with a similar analytical approach as secondary outcomes.
The alpha value was set at 0.05. SPSS version 11 was used (Chicago, IL, USA).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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). During the study period, patients did not report changes in lifestyle issues, including exercise, diet, smoking, and medications. Furthermore, no major changes in BMI were observed for any group [0.1 ± 0.7; 95% CI, –0.1 to 0.4; 0.0 ± 0.8, 95% CI, –0.4 to 0.4; and 0.3 ± 0.7 kg/m2, 95% CI, 0.0 to 0.6 mean differences for control (N = 24), SPT (N = 21), and IPT (N = 20), respectively, P > 0.56]. No adverse events or side-effects were reported in any of the three treatment groups.
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The covariance analysis showed a statistically significant treatment effect (P = 0.003, Model R2 = 0.86, N = 65). A reduction of CRP concentrations was observed in both treatment groups when compared with the untreated control. The SPT group showed a difference in CRP at 2 mos of 0.5 ± 0.2 mg/L (95% CI, 0–0.9, P = 0.030, Fig. 1, Table 2) compared with the untreated control group. The respective value for the IPT group was 0.8 ± 0.2 mg/L (95% CI, 0.3–1.2, P = 0.001). When the analysis was repeated with age, gender, body mass index, ethnicity, and cigarette smoking status included in the model as covariates, the results remained unchanged. SPT (P = 0.048) and IPT (P = 0.002) groups showed a greater reduction in CRP concentration compared with the control (Model R2 = 0.89, N = 65). Cigarette smoking status, however, approached statistical significance (P = 0.057), and further analysis indicated a significant interaction with the treatment group (P = 0.019). Post hoc testing revealed that CRP reductions were statistically significant to the control for both treatments only in the non-smokers (P = 0.048 SPT, P = 0.011 IPT, respectively) (Fig. 2). In the smoking subgroup, only IPT patients showed an important decrease (P = 0.030) compared with the controls.
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, Table 2). These findings were also confirmed after adjustment for possible confounders. Cigarette smoking was associated with the treatment groups (P = 0.021). Non-smokers of the IPT group showed differences only in IL-6 concentrations when compared with the controls (P = 0.005) and with the SPT group (P = 0.002).
Lipid levels remained mostly unchanged. We observed, however, a 0.3 ± 0.1 mmol/L (95% CI, 0.01 to 0.6; P = 0.05) decrease of total cholesterol in the IPT group when compared with the SPT group (Fig. 1). A within-group analysis showed a reduction in total cholesterol of 0.3 mmol/L (95% CI, 0.1 to 0.5; P = 0.004) in the IPT group together with a decrease in LDL of the same magnitude (0.3 mmol/L; 95% CI, 0.05 to 0.5; P = 0.019) (Table 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS & METHODSRESULTSDISCUSSIONREFERENCES |
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). During the study, no important changes in lifestyle, habits, medical health, or medications were detected. This indicates that severe, generalized periodontitis in these otherwise healthy individuals contributed to their systemic inflammatory burden. Proposed mechanistic explanations include: (i) the local, infection-driven production of inflammatory mediators (IL-1, IL-6) ‘dumped’ into the systemic circulation (Offenbacher et al., 1981; Graves, 1999); (ii) the ability of periodontal pathogens and/or their toxins to disseminate and thus induce a distant inflammatory response (Herzberg and Weyer, 1998; Haraszthy et al., 2000); and (iii) a combination of the above. These results, however, do not allow for generalization to periodontal patients suffering from less severe and/or more localized forms of disease. Data will have to be confirmed and expanded in larger trials if we are to better understand what proportion of the 10–15% of subjects suffering from severe periodontitis have increased systemic inflammation as a result of this chronic infection (Papapanou, 1996).
As indicated, this study was designed to detect changes in CRP concentrations only. A serious limitation of these preliminary results lies in the small number of subjects included. The baseline CRP and IL-6 concentrations appeared somehow unbalanced among the 3 study groups. The nature of the statistical analysis (covariance), however, and the inclusion of the main determinants of CRP and IL-6 serum concentrations (age, gender, body mass index) did not undermine our conclusions. Cigarette smoking was the only parameter to affect the systemic host response. The fact that smokers’ CRP concentrations responded to IPT and not SPT treatment supports the notion that periodontitis contributed to the increased inflammatory burden of the smokers as well. Further research in this matter is needed, however.
Periodontitis is a chronic biofilm-centered infection (Williams, 1990). It is relatively insensitive to the effects of systemic antibiotics, and its treatment requires, in the first instance, the removal of the biofilm on the root surface by professional mechanical instrumentation.
In the IPT group, a local antibiotic was utilized to supplement the mechanical action of scaling and root planing, to allow for the achievement and maintenance of high concentrations of the medication in the periodontal pockets without reaching detectable levels in the serum (Paquette and Santucci, 2000). Previous investigations have indicated that such a treatment regimen might lead to better control of periodontal infections and reduction in gingival inflammation (Hanes and Purvis, 2003). Interestingly, the adjunctive periodontal effect of the application of minocycline microspheres was particularly evident in smokers (Paquette et al., 2003), an observation that agrees well with the current one that IPT, but not SPT, was effective in decreasing systemic inflammation in smokers. Although a possible systemic effect of the antibiotic cannot be completely ruled out, the facts that (i) the total applied dose was 80 ± 25 mg per patient, (ii) the antibiotic was delivered from the controlled delivery platform over a 21-day period, and (iii) minocycline concentrations in serum have been shown to remain below detection level following this treatment regimen (Paquette and Santucci, 2000) make it unlikely that the observed effect may have been due to a systemic effect of minocycline. A reduction in systemic IL-6 concentration, which is known to be produced locally in the diseased periodontium (Irwin and Myrillas, 1998) and is the main inducer of the acute phase response (Gabay and Kushner, 1999), was detected only in the IPT group and might represent the added beneficial effect of such a treatment regimen.
Lipid marker changes were insignificant between SPT and control groups. IPT, in contrast, showed a greater reduction in total cholesterol compared with SPT but not with the untreated control. Descriptive analysis showed that some reductions of total and LDL cholesterol were present within the IPT group (Fig. 1).
We cannot exclude that pure chance might stand behind these findings, even though a biologically plausible effect of periodontal infections on the metabolic state of an individual has been validated through a series of investigations. A significant association between periodontitis and cholesterol has been reported (Katz et al., 2002). The inflammatory local production of cytokines (IL-1, TNF-
) and its effect on other systemic mediators (IL-6) might induce alterations of lipid metabolism, such as increased LDL and triglycerides, due to increased hepatic lipogenesis, lipolysis from adipose tissue, or reduced blood clearance (Iacopino and Cutler, 2000). Bacterial toxins (LPS) can also induce changes in cholesterol concentrations (Uchiumi et al., 2004) (reduced HDL and increased LDL) (Pussinen et al., 2004) or target glucose metabolism and produce a state of insulin resistance (Fernandez-Real and Ricart, 2003). Further investigations are needed for further exploration of the relationship among periodontitis, periodontal therapy, and lipid metabolism.
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ACKNOWLEDGMENTS |
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Received April 1, 2004; Last revision December 8, 2004; Accepted December 12, 2004
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REFERENCES |
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