TOBACCO USE AND PERIODONTAL DISEASE

PATIENT CARE II

 

TOBACCO USE AND PERIODONTAL DISEASE

  INTRODUCTION

             Smoking is often associated with leukoplakia and oral cancer in dentistry. However, there is scientific evidence showing that smokers are even more likely to have periodontal disease than malignant or premalignant lesions. In addition, several studies suggest that prevalence of periodontal disease is higher in smokers as compared to non-smokers¹. Haber et al, found that 51% of periodontitis in the 19-30 years old group and 32% of periodontitis in the 31-40 years old group are associated with smoking¹.

            Until recently, the effects of smoking on periodontal disease progression, its prevalence and severity have been inconclusive. However, the mechanisms of action exerted by tobacco on periodontium are still under investigation. The purpose of this paper is to research some of these mechanisms and to describe the clinical significance of knowing the pathogenesis of periodontal disease in smokers for dental hygiene care.

 HISTORICAL OVERVIEW

             The effects of smoking on periodontal health have been studied in the dental literature for at least four decades^2. In the past, it was believed that the effects of cigarette smoking on the periodontium were indirect and caused by inadequate oral hygiene and increased plaque accumulation among smokers relative to non-smokers³. Current epidemiological studies have shown strong association between smoking and the prevalence and severity of periodontitis. Some studies even suggest that the effect of smoking is a direct one and not due simply to poor oral hygiene and increased dental plaque in smokers⁴.

 CLINICAL FINDINGS

             Prior to discussing how tobacco smoking affects the periodontium, the clinical assessment data associated with tobacco smoking are described to demonstrate a strong association between the two. Clinical differences between smokers and non-smokers include gingival bleeding, periodontal pocket depth, number of diseased sites, clinical attachment loss, alveolar bone loss, recession and response to periodontal therapy.

            On periodontal assessment, smokers present with less gingival bleeding, redness, and exudate suggesting less pronounced gingival inflammatory response that may be due to either vasoconstriction, or the inhibition of the immune response caused by tobacco^{5, 6, 7, 8}.

            In spite of less pronounced gingival bleeding, the severity of periodontal disease appears to be higher in smokers than non-smokers^{9, 10, 11, 12}. Studies also show that the severity of periodontitis is directly proportional to the amount of tobacco consumed^{11, 12}.

            Different means of measuring the severity of periodontal disease show consistent results. One of such measurements, periodontal pocket depth, is shown to be higher in smokers^{13, 14, 15, 1, 4, 16, 10, 1}. Some studies also found that smokers have proportionately more pockets in the maxillary lingual and anterior regions that non-smokers^{10, 2}. Moreover, not only do smokers have deeper pockets, but they also have a higher number of diseased sites^{14, 17, 4, 18, 16, 2, 19}.

            Another measurement of periodontal disease severity—clinical attachment loss—is also shown to be greater in smokers^{12, 20, 11, 17, 21} and this association is dose-dependent^{21, 12}. Several studies found increased alveolar bone loss in smokers^{7, 22, 18, 9} that is shown to be both time-²³ and dose-dependent^{24, 23}. These data is consistent with the findings that show greater tooth loss in smokers as compared to non-smokers^{13, 25, 15}, also dose-dependent²⁵.

            In addition to greater probing depths, alveolar bone loss and tooth loss, smokers also tend to have more recession²⁰ that tends to progress more rapidly following periodontal therapy in smokers^{26, 6}. The usual location of recession smokers is the maxillary and mandibular anterior segments with resulting open embrasures and fibrotic roiled margins².

            Smokers have reported less frequent brushing and flossing than non-smokers²⁷ that may contribute to a greater amount of plaque; however, the data on amount of plaque and calculus between smokers and non-smokers are still inconclusive.

            In addition to higher severity of periodontal disease, smokers show less response to periodontal therapy, both surgical^{26, 28} and non-surgical^{29, 14, 6, 28} than do non-smokers. This is expressed in less reduction in gingival pocket depth^{30, 6, 28, 14, 31, 8} and in number of diseased sites¹⁴, less clinical attachment gain^{6, 26, 28, 31, 8}, less reduction in the number of periodontal pathogens^{32, 6}, and re-pocketing within one year of surgical treatment³³.

            There are many current research studies that demonstrate smoking as a significant risk indicator for clinical signs of periodontal disease.

MECHANISMS OF PERIODONTAL DISEASE PROGRESSION IN SMOKERS

            Although the pathogenesis of periodontitis in smokers is poorly understood, there are studies suggesting that smoking may affect the microflora of the periodontal pocket and/or the host response. It may be affecting the host through any of the following mechanisms: inhibition of neutrophil function, impairment of antibody response to periodontal pathogens, diminishing of gingival fibroblast function, altering osteoblast function, and vasoconstriction.

Due to the paper length restriction, only the microbiology and the first three mechanisms will be discussed. These are chosen because of their importance in the host response and their new research developments.

 Microbiology of periodontal disease in smokers

In the past, there have been many studies conducted on differences in oral microflora between smokers and non-smokers. The results have been contradictory—some studies concluded there are no significant differences, while others indicated higher numbers of periodontal pathogens in smokers. In this paper, we decided to look at the most recent studies on the subject to determine if any conclusion has been achieved.

            Out of six studies we looked at, all dated 1992-1998, most of the studies did not find any statistically significant difference in periodontal pathogens between smokers and non-smokers^{29, 34, 14, 13}. One of these studies (Stoltenberg et al.) controlled for other variables such as age, sex, plaque, and calculus¹³. Two of the studies (by Renvert et al.²⁹ and by Preber et al.¹⁴) were conducted with a relatively small number of subjects—32 and 28, and none of the samples was completely randomized and representative of the general population. Of interest is the study by Zambon et al.¹¹., which found significantly greater (1.5 times) risk of infection with Bacteroides forsythus and significantly higher levels of this bacteria in smokers compared to non-smokers. The same study also found significantly higher (3.1 times) levels of Actinobacillus Actinomycetemcomitans in smokers. Although this is the only study showing greater risk of infection with certain periodontal pathogens in smokers, this study had the largest number of subjects (1,426) compared to others that makes it impossible to ignore. This study also found the risk of infection with B.forsythus to be dose-related—higher in heavy smokers. Interestingly, they also discovered that former smokers were more (1.5 times) likely to harbor subgingival B.forsythus than non-smokers.

Several studies also investigated the differences in microflora between smokers and non-smokers following non-surgical periodontal treatment. The results found by Grossi et al.⁶ appear to correspond with the data in the study by Zambon et al¹¹. Although there were no statistically significant differences at the baseline, the study found statistically significantly lesser reduction in periodontal pathogens in subgingival plaque of smokers three months following non-surgical treatment. No statistically significant differences were found in the two other studies (Preber et al. and Renvert et al.); however, Preber et al. “found .A. Actinomycetemcomitans to be more difficult to eradicate among smokers as compared to non-smokers although this difference was not statistically significant”²⁹.

            The analysis of the results of the above mentioned studies proves them to be still inconclusive because in spite of the number of studies showing no difference in microflora, there is a fair indication that certain periodontal pathogens are more likely to infect smokers than non-smokers. Therefore, more research is needed in this area.

 Effects on the Host Response and Periodontium

            Since the majority of the research studies have not demonstrated any conclusive findings on the effects of tobacco smoking on the ecology of the oral cavity, some investigators have examined the role of smoking in altering the periodontal host response.. In general, smoking could contribute to periodontal destruction by altering the host response through the two mechanisms: 1) tobacco smoking could impair the normal function of the host's immune system and 2) the alteration of the host response by tobacco could result in destruction of the surrounding healthy periodontium³⁵.

Tobacco effects on the immune system

            Smoking hampers both primary and secondary immune responses. Several studies have shown that tobacco smoke can impair the functions of the polymorphonuclear leukocytes (PMNs) by reducing their phagocytic activity, motility, and/or chemotactic migration (the primary immune response). Tobacco smoke and its water soluble components have been shown to adversely affect the chemotactic and phagocytic ability of PMNs. MacFarlane et al (1992) conducted an experiment that showed no chemotactic defect of PMNs in smokers with refractory periodontitis, but significantly (p<O.OO1) impaired phagocytic ability³⁶. All subjects were controlled for confounding variables such as environmental factors that may contribute to periodontitis, even subgingival flora was analyzed for the distribution of putative pathogens that might contribute to refractory periodontal disease. However, the study was conducted with only 3I subjects and the control group of 12, with Staphylococcus aureus 502A as the target bacteria for the assay of phagocytosis. With a small sample size and specific target organism, the results of this study need to be interpreted with caution when applying to the human oral environment.

In another study by Pabst et al (1995), nicotine preferentially affected oxygen-dependent killing microorganisms³⁷. Specifically, nicotine inhibited the production of oxygen radicals (superoxide and peroxide) that was measured by reduction in cytochrome C. The production of peroxide was inhibited by 70% with 0.1% nicotine and by 90% with 0.3% nicotine. By inhibiting the production of oxygen radicals, nicotine reduces the antimicrobial activity of PMNs, thus promoting bacterial colonization and periodontitis. In addition, the study showed that nicotine reacted directly with oxygen radicals by absorbing superoxide and preventing it from reducing the cytochrome c. Nicotine shows the same inhibitory effect on oxygen radicals of monocytes. However, the experiment showed that nicotine had no cytotoxic effect on neutrophils and did not affect their phagocytosis. By conducting independent assays of superoxide production, peroxide production, and oxygen consumption by neutrophils and monocytes, the study demonstrated that the effects of nicotine on these cells function was not an artifact of one particular assay for oxygen radical release. The weaknesses of the study are: it was conducted in vitro, which is not a true representation of the real conditions in which the cells normally operate; and the short exposure to nicotine is not an accurate representation of the damaging effect of many years of exposure tobacco in a smoker. Hence, the result of nicotine having no cytotoxic effects with short time exposure needs to be viewed with caution. More longitudinal studies are needed to investigate the cytotoxic effects of nicotine on host defense cells.

Nicotine can affect the chemotactic migration of neutrophils to the site of infection, one of the earliest critical events in the host response. This process involves two classes of adhesion molecules. L-selectins are expressed on the surface of neutrophils and are responsible for a primary loose tethering of the neutrophil to the endothelial cell enabling them to "roll" along the vessel wall. CD11/18 integrins allow for a firmer attachment and subsequent migration of the neutrophils to the infected tissue³⁸. In their study, Ryder et al found an approximate 75% shedding of L-selectin in both smokers and non-smokers with no marked difference between groups at 1 to 5 minute exposures to smoke. In addition, cigarette exposure resulted in a 15% to 20% increase in CD11/18 expression in both smokers and nonsmokers. The elevation of CD1 1/18 integrin expression may promote initial migration of neutrophils into the periodontal tissues. Also, the CD18 mediated firm adherence of neutrophils to endothelial cells, connective tissue matrix and other cells may create pockets between the neutrophil and matrix. This can exclude substances (e.g. superoxide dismutase) that would normally neutralize the destructive enzymes and oxidative burst products of neutrophils. Future research in new treatment approaches, such as using antioxidants to partially block the upregulation of CD18 expression in order to attenuate the tissue destruction by the neutrophils in periodontal disease, is implicated. The physiological relevance of the vitro smoke box exposure was demonstrated by comparing the levels of nicotine exposure in the study to acute and chronic levels of nicotine in saliva and gingival crevicular fluid. The levels of nicotine in the smoke box system fell somewhere between acute and chronic levels of nicotine in saliva. Therefore, the study provided physiologically relevant doses of acute tobacco smoke, despite being done in vitro.

Not only nicotine affects the migration of neutrophils, but it may also impair the chemotactic activities of leukocytes. Two prominent inflammatory mediators, interleukin -1b (IL-1b, responsible for activating osteoclasts and fibroblasts) and prostaglandin E₂ (PGE₂, activates collagenase) have been implicated in progressive periodontitis. One study have found that PGE2 secretion by peripheral blood mononuclear cells (PBMC) was enhanced when treated with nicotine and P. gingivalis LPS relative to P. gingivalis LPS alone³⁹. In contrast, nicotine significantly downregulated IL-1b secretion by gingival mononuclear cells (GMC, includes T-cells, B-cells, and macrophages) relative to medium alone and had no effect on PGE2 secretion by GMC. These results indicate that while nicotine can stimulate PBMC to secrete PGE2, they cannot activate further the mononuclear cells extracted from gingiva, possibly due to maximal previous stimulation in the periodontitis lesion³⁹. It is suggested that the reduction in IL-1b allows the chronic periodontal infection to be inadequately challenged and consequently further soft and hard tissue damage. An investigation by Pabst et al (1995) mirrors the finding that 0.1% nicotine inhibits IL-1b secretion by GMC³⁷. However, both studies were conducted in vitro, thus it is difficult to extrapolate the findings to the oral cavity conditions.

Smoking is also associated with an altered antibody response (secondary immune response). McGuire et al suggested the altered lymphocyte proliferation is due to depressed DNA synthesis⁴⁰. Other studies have measured the levels of IgG and IgA as an indicator of local immunologic reactivity to periodontal diseases. The study by Basu et al found that subjects that had periodontitis had higher concentration of IgG and lower IgA before oral hygiene therapy and periodontal surgery than afterwards. The high concentration of IgG was attributed to the local IgG response to antigenic challenge of bacterial plaque and greater leakage through diseased pocket epithelium⁴¹. Thus, the results for IgA conflict with the past studies. Basu et al mention that another study by Lindstrom and Folke (1973) found higher levels of IgA that was attributed to the increased leakage of serum 7S IgA from the inflamed periodontal tissues. Basu et al suggested that the lowered IgA was due to the IgA forming large complexes and aggregating with products of bacterial plaque and exudate inactive periodontal disease, or it could be caused by the dilution of excessive saliva production in response to the inflammation. Basu et al only used 12 subjects, which is a very small sample size. It is difficult to compare the studies because they utilize different methods of selecting patients with and without periodontal diseases. More controlled studies on this topic are needed. A more recent study by Bennet et al (1992) investigated salivary IgA levels in normal subjects, tobacco smokes and patients with minor aphthous ulcerations ⁴². They found that tobacco smokers showed a decrease in IgA concentrations when compared with a matched control group. The result was attributed to an

immunosuppressive effect of the combustion products of tobacco and the possibility of the intraoral neoplastic incidence in smokers. The strength of this study is that it eliminated and controlled confounding variables such as caffeine, alcohol, and drug consumption as much as possible. Even the salivary flow rate of subjects was closely matched between the experimental and control groups. There are several studies that confirm the suppression of IgA in tobacco smokers.

 Destructive effect of tobacco on the host response

The host response can be affected by tobacco through altering the gingival fibroblasts leading to the destruction of the healthy periodontium. Normal function of gingival fibroblasts is essential for maintenance of the gingival extracellular matrix. Not only they secrete collagen, thus playing an important role in regeneration and maintenance of connective tissue, but they also participate in collagen degradation by secreting collagenase. They also produce an adhesive glycoprotein fibronectin, which mediates the attachment of fibroblasts and other cells, as macrophages, to the extracellular matrix, thus participating in cell migration and wound healing⁴³. The production of alkaline phosphatase by fibroblasts precedes bone mineral deposition⁴⁴.

            Several studies have been conducted to investigate the effect of nicotine on fibroblast proliferation and attachment in vitro. The results were not consistent through the studies. For example, in the study by Raulin⁴⁵, the fibroblasts attached and grew on glass and root surfaces at all concentrations of nicotine, while the study by Giannopoulou⁴⁴ showed dose-dependent inhibition of proliferation and attachment. On the contrary, Peacock et al., in their study, discovered time- and concentration-dependent increase in both the attachment and proliferation⁴⁶. Several studies also noted changes in morphology of fibroblasts following nicotine exposure; however, these changes also were not consistent among the studies. Thus, Peacock found fibroblasts to exhibit more flattened appearance, which is consistent with the increased attachment capabilities in his study. At the same time, other studies found the disruption of normal orientation of cells and vacuolization of the cytoplasm, which may be due to a general response of the cells to injury, or to the uptake and storing nicotine in vesicles by fibroblasts^{43, 44, 45}.

            Some studies showed the consistent decrease in collagen production^{43, 47}, and another study showed the inhibition of fibronectin production and an increase in collagenase production by fibroblasts following nicotine exposure, both of which were dose-dependent. These findings may signify the impeded regeneration and increased degradation of collagen⁴³. The study by Giannopoulou also has shown an inhibition in alkaline phosphatase production by fibroblasts and impeded chemotaxis in the presence of nicotine, both dose-dependent. This may have an effect on bone regeneration and maintenance by impeding bone mineral deposition.

            There seems to be more evidence in proof of inhibited regenerative capabilities of fibroblasts by nicotine, at least by impeding collagen production. However, these results should be interpreted with caution because most of the studies were conducted in vitro and thus cannot be readily transferred to human tissues. The studies concerning fibroblast attachment and proliferation are inconclusive and need further investigation. One possible reason for the inconsistency in results may be the fact that fibroblasts for different studies were derived from different sources: Peacock and Tipton used gingival fibroblasts⁴³, while Giannopoulou used periodontal ligament fibroblasts⁴⁴, and Raulin used human foreskin fibroblasts⁴⁵. Also, the attachment was measured towards the plastic or glass substrate, except for one study that used root surfaces for this purpose. Same studies should be conducted again, but with the same one type of fibroblasts to be conclusive.

 In summary tobacco smoking is a major risk factor in the progression of periodontal diseases. Its effect may be an alteration of local microflora and/or systemic alteration of the host response. The changes in the host response may impair the neutralizing function of the immune cells and/or give rise to enhanced destruction of healthy periodontal tissues through its effect on fibroblasts.

 

CONCLUSION

 Tobacco smoking exerts a biological effect on periodontal bone and tissue, increasing the risk of progressive periodontitis. Studies have shown clinical differences in the smokers with periodontitis compared to non-smokers, which include greater frequency of deep pockets, alveolar bone loss and attachment loss, greater severity, prevalence, and recession, higher number of furcations, and lesser bleeding on probing. By having a greater understanding of the mechanisms and pathogenesis of periodontal diseases in tobacco smokers, a clinician can become aware of the clinical changes that may be assessed. Smoking can mask the early signs of periodontal disease by suppressing or blocking the inflammatory response which can lead to later diagnosis of the disease.² Research findings of the strong association between periodontitis and smoking suggest that the smoking status is a clinically useful predictor of future periodontal disease. Therefore, tobacco smoking must be considered in the prevention, assessment, diagnosis, planning and treatment of periodontal disease. Also, since smoking not only contributes to periodontal disease but spurs the development of oral cancer, smoking cessation should be considered in the treatment of periodontitis and be a part of health prevention in dentistry. Tobacco smoking is the single most important changeable environmental factor, the elimination of which can provide beneficial healing progress in periodontal diseases.

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