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Periodontal Disease is Related to Local and Systemic Mediators of Inflammation
DIAGNOSIS/TREATMENT/PROGNOSIS
ARTICLE ANALYSIS & EVALUATION ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Local and systemic biomarkers in gingival crevicular fluid increase odds of periodontitis. Fitzsimmons TR, Sanders AE, Bartold PM, Slade GD. J Clin Periodontol 2010;37(1):30-6.
REVIEWER Ananda P. Dasanayake, BDS, MPH, PhD, FACE
PURPOSE/QUESTION The authors attempted to study the independent and combined effects of local (IL-1b) and systemic (CRP) inflammatory biomarkers in gingival crevicular fluid (GCF) on the risk of periodontitis.
SOURCE OF FUNDING Government: National Health and Medical Research Council (NHMRC) of Australia and NHMRC Sidney Sax Public Health Fellowship.
TYPE OF STUDY/DESIGN Case-control study.
LEVEL OF EVIDENCE Level 2: Limited-quality, patientoriented evidence
STRENGTH OF RECOMMENDATION GRADE Not applicable
J Evid Base Dent Pract 2010;10:246-247 1532-3382/$36.00 Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jebdp.2010.09.006
Periodontal Disease is Related to Local and Systemic Mediators of Inflammation SUMMARY Subjects Data for this case-control study came from the 2004-2006 Australian National Survey of Adult Oral Health. A total of 5505 adults underwent standardized oral examinations during the above survey. From that sample, 430 subjects were identified as having moderate to severe periodontal disease. Noncases (509) were randomly selected using frequency matching (with state/territory as the matching variable) to ensure adequate numbers of cases and noncases from each geographical area. Age or gender distribution was not reported for either group.
Key Exposure/Study Factor Key exposures in this study were local (interleukin [IL]-1b) and systemic (C-reactive protein [CRP]) inflammatory biomarkers in gingival crevicular fluid (GCF). GCF was collected from 4 randomly selected sites (2 sites with probing depths of at least 4 mm and 2 sites with shallow probing for the study cases, and 4 random sites with shallow pockets in the noncases). GCF was collected using paper strips, and IL-1b and CRP levels were measured using enzyme-linked immunosorbent assay (ELISA). It is important to note that the GCF samples were collected after probing, leaving the possibility of contaminating GCF with blood. The authors mentioned in passing that these contaminated samples were discarded, but how many or their case/control status was not given.
Main Outcome Measure Primary outcome for this analysis was the moderate to severe periodontal disease (PD) status of the subject. Subjects were identified as having moderate to severe PD based on having 2 or more interproximal sites with 4 mm or more of clinical attachment loss and 2 or more interproximal sites with pocket depth of 5 mm or more. It is important to note that the third molars were excluded from the case definition, potentially underestimating the true periodontal inflammation.
Main Results The crude association (odds ratio [OR]) between GCF IL-1b levels (the highest vs the lowest tertile) and moderate to severe PD was 2.4 (95% confidence interval [CI] = 1.7-3.4). A dose-response was seen between IL-1b levels and PD risk. When this association was adjusted for a series of potential confounders (sociodemographic characteristics, self-reported smoking, and history of chronic conditions), the strength of the association was attenuated to an OR of 1.8 (95% CI = 1.2-2.6). The crude association between CRP (detectable vs nondetectable) was 1.9 (95% CI = 1.5-2.5), and the adjusted association was 1.7 (95% CI = 1.3-2.3). When the combined effect of IL-1b and CRP levels on moderate to severe PD was evaluated, although the subjects with the highest IL-1b levels and detectable CRP values were 2 times more likely to have moderate to severe PD
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
(OR = 1.9; 95% CI = 1.2-2.9), there apparently was no statistically significant effect modification.
Conclusions Increased odds of moderate to severe PD was associated independently with elevated levels of both IL-1b and CRP levels in the GCF samples. Known risk factors for PD such as age, gender, and smoking status were also observed to be significantly associated with PD, lending external validity to the reported findings.
COMMENTARY AND ANALYSIS The broader research question addressed here is the association between local and systemic inflammation (as measured using specific biomarkers) and the moderate to severe PD among adults. As periodontal disease is related to both infection and inflammation, further evaluation of the role of each etiologic component is of value. This study addressed the role of host inflammation related to PD. The authors chose to use IL-1b and CRP levels in GCF samples as biomarkers of local and systemic inflammatory response. If locally produced IL-1b in response to PD triggers CRP production in a distant site, such as the liver, it is useful to evaluate both the independent and combined effect of IL-1b and CRP on the risk of moderate to severe PD. To understand the above, ideally, one needs to longitudinally evaluate IL-1b and CRP levels in sufficient numbers of subjects as they transform from health to moderate to severe periodontal disease over time. This, however, is a logistical challenge. The authors chose a feasible alternative approach by using cross-sectional data (exposure and outcome data are measured at the same time) collected in a National Oral Health Survey. A sufficiently large number of subjects (430) with moderate to severe PD by their definition were compared with a randomly selected group with no PD (509) in a nested case-control fashion. IL-1b and CRP levels measured once in 4 sites per subject (2 sites with and without disease in cases, and 4 randomly selected sites in controls) were compared between cases and controls. By obtaining just one measurement of biological variables such as IL-1b and CRP subsequent to the development of the disease, investigators limited the inferences they could draw from the study, and now can only speculate that higher biomarker levels may increase the odds of PD, whereas the reverse may also be a possibility. Inclusion of GCF samples obtained from less severe disease sites from cases may have attenuated the true association as well. Furthermore, exclusion of third molars may also have added measurement errors in terms of the outcome variable, the PD status. Finally, only 3 sites per tooth
Volume 10, Number 4
were examined to measure the true PD status of the subject, once again underestimating the PD status among cases and controls (some controls may have been real cases). Despite the potential errors in measuring IL-1b and CRP levels as well as PD status, they observed a statistically significant independent effect of higher levels of IL-1b and CRP in relation to moderate to severe PD. The observed association remained significant even after controlling for the known risk factors for PD, although data related to some of the confounders are of questionable validity, as they are self-reported (ie, smoking). It is important to evaluate the effect of potential measurement errors mentioned earlier on the observed strength of the association. Misclassification of the outcome variable (PD) and the primary exposure variables can drive the OR in either direction, either toward, or away from the null value of 1. If one were to make the argument that the measurement errors were randomly distributed among cases and controls, the direction of bias would be towards the null, showing that the true association was even greater than the reported observed associations. However, underestimating the inflammatory mediator levels among cases by including both shallow and deep sites for collecting GCF, they clearly underestimated the true level of inflammatory mediators in relation to moderate to severe disease. If we assume for a moment that the reported association is in fact closer to the truth, that the increased local and systemic inflammatory biomarker levels lead to moderate to severe PD, what will be the clinical or public health significance of this finding? First, these inflammatory biomarkers were nonspecific, as the authors also pointed out, and could very well be related to the other concurrent systemic conditions. On the other hand, as the measurements were a snapshot (or of cross-sectional nature), it is hard to comment on the predictive nature of these measurements on the future PD status of the subject. As stated earlier, longitudinal studies are needed to shed more definitive light on the reported association and its use within clinical and/or public health settings.
REVIEWER Ananda P. Dasanayake, BDS, MPH, PhD, FACE Professor & Director Graduate Program in Clinical Research New York University College of Dentistry 250 Park Ave South, 6th Floor - Room 646 New York, NY 10003-1402 Tel: 212-998-9631 Fax: 212-995-4788 [email protected]
247
ARTICLE ANALYSIS & EVALUATION ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Local and systemic biomarkers in gingival crevicular fluid increase odds of periodontitis. Fitzsimmons TR, Sanders AE, Bartold PM, Slade GD. J Clin Periodontol 2010;37(1):30-6.
REVIEWER Ananda P. Dasanayake, BDS, MPH, PhD, FACE
PURPOSE/QUESTION The authors attempted to study the independent and combined effects of local (IL-1b) and systemic (CRP) inflammatory biomarkers in gingival crevicular fluid (GCF) on the risk of periodontitis.
SOURCE OF FUNDING Government: National Health and Medical Research Council (NHMRC) of Australia and NHMRC Sidney Sax Public Health Fellowship.
TYPE OF STUDY/DESIGN Case-control study.
LEVEL OF EVIDENCE Level 2: Limited-quality, patientoriented evidence
STRENGTH OF RECOMMENDATION GRADE Not applicable
J Evid Base Dent Pract 2010;10:246-247 1532-3382/$36.00 Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jebdp.2010.09.006
Periodontal Disease is Related to Local and Systemic Mediators of Inflammation SUMMARY Subjects Data for this case-control study came from the 2004-2006 Australian National Survey of Adult Oral Health. A total of 5505 adults underwent standardized oral examinations during the above survey. From that sample, 430 subjects were identified as having moderate to severe periodontal disease. Noncases (509) were randomly selected using frequency matching (with state/territory as the matching variable) to ensure adequate numbers of cases and noncases from each geographical area. Age or gender distribution was not reported for either group.
Key Exposure/Study Factor Key exposures in this study were local (interleukin [IL]-1b) and systemic (C-reactive protein [CRP]) inflammatory biomarkers in gingival crevicular fluid (GCF). GCF was collected from 4 randomly selected sites (2 sites with probing depths of at least 4 mm and 2 sites with shallow probing for the study cases, and 4 random sites with shallow pockets in the noncases). GCF was collected using paper strips, and IL-1b and CRP levels were measured using enzyme-linked immunosorbent assay (ELISA). It is important to note that the GCF samples were collected after probing, leaving the possibility of contaminating GCF with blood. The authors mentioned in passing that these contaminated samples were discarded, but how many or their case/control status was not given.
Main Outcome Measure Primary outcome for this analysis was the moderate to severe periodontal disease (PD) status of the subject. Subjects were identified as having moderate to severe PD based on having 2 or more interproximal sites with 4 mm or more of clinical attachment loss and 2 or more interproximal sites with pocket depth of 5 mm or more. It is important to note that the third molars were excluded from the case definition, potentially underestimating the true periodontal inflammation.
Main Results The crude association (odds ratio [OR]) between GCF IL-1b levels (the highest vs the lowest tertile) and moderate to severe PD was 2.4 (95% confidence interval [CI] = 1.7-3.4). A dose-response was seen between IL-1b levels and PD risk. When this association was adjusted for a series of potential confounders (sociodemographic characteristics, self-reported smoking, and history of chronic conditions), the strength of the association was attenuated to an OR of 1.8 (95% CI = 1.2-2.6). The crude association between CRP (detectable vs nondetectable) was 1.9 (95% CI = 1.5-2.5), and the adjusted association was 1.7 (95% CI = 1.3-2.3). When the combined effect of IL-1b and CRP levels on moderate to severe PD was evaluated, although the subjects with the highest IL-1b levels and detectable CRP values were 2 times more likely to have moderate to severe PD
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
(OR = 1.9; 95% CI = 1.2-2.9), there apparently was no statistically significant effect modification.
Conclusions Increased odds of moderate to severe PD was associated independently with elevated levels of both IL-1b and CRP levels in the GCF samples. Known risk factors for PD such as age, gender, and smoking status were also observed to be significantly associated with PD, lending external validity to the reported findings.
COMMENTARY AND ANALYSIS The broader research question addressed here is the association between local and systemic inflammation (as measured using specific biomarkers) and the moderate to severe PD among adults. As periodontal disease is related to both infection and inflammation, further evaluation of the role of each etiologic component is of value. This study addressed the role of host inflammation related to PD. The authors chose to use IL-1b and CRP levels in GCF samples as biomarkers of local and systemic inflammatory response. If locally produced IL-1b in response to PD triggers CRP production in a distant site, such as the liver, it is useful to evaluate both the independent and combined effect of IL-1b and CRP on the risk of moderate to severe PD. To understand the above, ideally, one needs to longitudinally evaluate IL-1b and CRP levels in sufficient numbers of subjects as they transform from health to moderate to severe periodontal disease over time. This, however, is a logistical challenge. The authors chose a feasible alternative approach by using cross-sectional data (exposure and outcome data are measured at the same time) collected in a National Oral Health Survey. A sufficiently large number of subjects (430) with moderate to severe PD by their definition were compared with a randomly selected group with no PD (509) in a nested case-control fashion. IL-1b and CRP levels measured once in 4 sites per subject (2 sites with and without disease in cases, and 4 randomly selected sites in controls) were compared between cases and controls. By obtaining just one measurement of biological variables such as IL-1b and CRP subsequent to the development of the disease, investigators limited the inferences they could draw from the study, and now can only speculate that higher biomarker levels may increase the odds of PD, whereas the reverse may also be a possibility. Inclusion of GCF samples obtained from less severe disease sites from cases may have attenuated the true association as well. Furthermore, exclusion of third molars may also have added measurement errors in terms of the outcome variable, the PD status. Finally, only 3 sites per tooth
Volume 10, Number 4
were examined to measure the true PD status of the subject, once again underestimating the PD status among cases and controls (some controls may have been real cases). Despite the potential errors in measuring IL-1b and CRP levels as well as PD status, they observed a statistically significant independent effect of higher levels of IL-1b and CRP in relation to moderate to severe PD. The observed association remained significant even after controlling for the known risk factors for PD, although data related to some of the confounders are of questionable validity, as they are self-reported (ie, smoking). It is important to evaluate the effect of potential measurement errors mentioned earlier on the observed strength of the association. Misclassification of the outcome variable (PD) and the primary exposure variables can drive the OR in either direction, either toward, or away from the null value of 1. If one were to make the argument that the measurement errors were randomly distributed among cases and controls, the direction of bias would be towards the null, showing that the true association was even greater than the reported observed associations. However, underestimating the inflammatory mediator levels among cases by including both shallow and deep sites for collecting GCF, they clearly underestimated the true level of inflammatory mediators in relation to moderate to severe disease. If we assume for a moment that the reported association is in fact closer to the truth, that the increased local and systemic inflammatory biomarker levels lead to moderate to severe PD, what will be the clinical or public health significance of this finding? First, these inflammatory biomarkers were nonspecific, as the authors also pointed out, and could very well be related to the other concurrent systemic conditions. On the other hand, as the measurements were a snapshot (or of cross-sectional nature), it is hard to comment on the predictive nature of these measurements on the future PD status of the subject. As stated earlier, longitudinal studies are needed to shed more definitive light on the reported association and its use within clinical and/or public health settings.
REVIEWER Ananda P. Dasanayake, BDS, MPH, PhD, FACE Professor & Director Graduate Program in Clinical Research New York University College of Dentistry 250 Park Ave South, 6th Floor - Room 646 New York, NY 10003-1402 Tel: 212-998-9631 Fax: 212-995-4788 [email protected]
247