Tobacco consumption and periodontal disease

Introduction

Tobacco smoking is at present considered as the single greatest environmental factor for disease and premature death in the western world. An impressive amount of scientific data has been accumulated demonstrating an unequivocal association between smoking and morbidity (^{Bartecchi et al., 1994)}. Concerning lungcancer and coronary heart disease the relationship may be considered as causual (^{US Department of Health, Education and Welfare, 1979} ; ^{US Department of Health and Human Services, 1982}).

There is also increasing evidence from recent years that tobacco smoking is closely linked to periodontal disease and may act as a major risk factor (^{Haber et al., 1993} ; ^{Bergström and Preber, 1994} ; AAP, Position paper, 1996 ; ^{Zambon et al., 1996} ; ^{Salvi et al., 1997}). The following review article will in a conscise form summarize our present knowledge on different aspects of tobacco consumption and periodontal disease.

Tobacco smoking and gingival inflammation

Although a possible connection between smoking and acute necrotizising ulcerative gingivitis (ANUG) was proposed already more than a century ago (^{Bergeron, 1859}), the first relation in modern time between smoking and periodontal disease was demonstrated by ^{Stammers (1944}) and ^{Pindborg (1947}) who reported smokers to have a higher prevalence of ANUG than non-smokers. This finding has been confirmed in later studies (^{Goldhaber and Giddon, 1964} ; ^{Kardachi and Clarke, 1974}) and recently a similar relationship has been reported between smoking and ANUG-like lesions in HIV-infected individuals (^{Swango et al., 1991}). The results from these studies are conclusive suggesting a clear association between smoking and ANUG.

Concerning the relationship between smoking and chronic gingivitis results from earlier epidemiologic studies have been contradictory. Some studies have reported less or no difference in gingival inflammation when smokers were compared to non-smokers (^{Ainamo, 1971} ; ^{Bergström and Floderus-Myrhed, 1983} ; ^{Feldman et al., 1983}) while other studies have reported a higher degree of gingival inflammation in smokers (^{Arno et al., 1958} ; ^{Alexander, 1970} ; ^{Preber and Kant, 1973} ; ^{Preber et al., 1980}). These later results are not surprising since smokers usually are found to harbour greater amount of plaque and/or calculus than non-smokers (^{Arno et al., 1958}, ^{Kristoffersen, 1970} ; ^{Alexander, 1970} ; ^{Ainamo, 1971} ; ^{Sheiham, 1971} ; ^{Preber and Kant, 1973} ; ^{Lavstedt, 1975} ; ^{Preber et al., 1980} ; ^{Feldman et al., 1983} ; ^{Ismail et al., 1983} ; ^{MacGregor, 1984}). Consequently much of smokers´ excess gingivitis might be explained by a greater amount of plaque primarily associated with an inferior oral hygiene (^{MacGregor, 1984} ; ^{MacGregor and Rugg-Gunn, 1984}). Recent studies that have controlled for plaque levels indicate that the gingival inflammation in smokers is clinically suppressed i.e. with similar amounts of plaque, smokers will not exhibit gingivitis as clearly as non-smokers (^{Bergström and Floderus-Myrhed, 1983} ; ^{Preber and Bergström, 1985a, 1986} ; ^{Bergström and Preber, 1986} ; ^{Bergström et al., 1988} ; ^{Bergström, 1991}). Furthermore from studies with an experimental gingivitis model, where the subjects have refrained from oral hygiene procedures for 3 to 4 weeks, smokers exhibited less gingival bleeding in spite of the same level of plaque accumulation (^{Bergström and Preber, 1986} ; ^Danielsen ).

These results which suggest a lower bleeding propensity for smokers (^{fig. 1}) might not be surprising according to the well known effect of nicotine excerting local vasoconstriction on peripheral circulation (^{Suter et al., 1983}). However they may be of clinical significance ; since bleeding on probing is considered an important clinical sign of periodontal disease and also acts as a criterium for periodontal treatment planning. Consequently if smokers´ lower bleeding propensity is not taken into consideration, there is an obvious risk for under-estimation and under-treatment of periodontal disease in smokers.

Tobacco smoking and periodontitis

Earlier epidemiological studies of a cross-sectional design were not conclusive regarding a possible relationship between smoking and periodontal disease (^{Ludwick and Massler, 1952} ; ^{Arno et al., 1958} ; ^{Solomon et al., 1968} ; ^{Summers and Oberman, 1968} ; ^{Sheiman, 1971}). However it should be borne in mind that although the reliability of these earlier studies may be regarded as rather low, they still have gathered important information and prepared the way for future studies.

During the last 15 years a number of well controlled studies on larger groups of populations using modern epidemiologic and statistical methods have unanimously demonstrated a clear relationship between smoking and periodontitis (^{Ismail et al., 1983} ; ^{Feldman et al., 1983} ; ^{Preber and Bergström, 1986} ; ^{Bergström and Eliasson, 1987} ; ^{Feldman et al., 1987} ; ^{Goultshin et al., 1990} ; ^{Ismail et al., 1990} ; ^{Haber and Kent, 1992} ; ^{Haber et al., 1993} ; ^{Bergström and Preber, 1994} ; ^{Grossi et al., 1994} ; ^{Linden and Mullally, 1994} ; ^{Grossi et al., 1995} ; ^{Martinez-Canut et al., 1995} ; ^{Mullally and Linden, 1996} ; ^{Zambon et al., 1996}). The results from these studies suggest smokers to have an inreased prevalence and severity of periodontitis, as reported by greater marginal bone loss, deeper periodontal pockets, more severe clinical attachment loss and more teeth with furcation problems (^{fig. 2} and ³). Concerning smokers´ greater radiographic bone loss, the difference will remain even after controlling for dental plaque, indicating an effect per se of smoking (^{Bergström and Eliasson, 1987} ; ^{Bergström and coll., 1991}).

Risk assessment. Attributable risk

Risk assessment has become increasingly important in the prevention of chronic diseases and has recently been applied to periodontal disease.

In 2 case-control studies, of a similar design, performed on samples of periodontitis patients (^{Preber and Bergström, 1986} ; ^{Haber and Kent, 1992}), the relative risk for smokers to attract the disease was calculated. Both studies reported the smoking attributable risk (odds ratio) to be between 2-2.5. ^{Grossi et al. (1994}) reported risk estimates of a similar magnitude (odds ratio = 2.4) on a large scale epidemiologic survey including 1 400 subjects. For severe periodontitis, the attributable risk increases to odds ratios between 5-14 depending of the level of disease and the smoking exposure (^{Bergström, 1989} ; ^{Haber and Kent, 1992} ; ^{Linden and Mullally, 1994}). Attributable risk estimates from recent studies are presented in ^{table l}.

Although an attributable risk of a magnitude around 2 may not look too impressive, it should be borne in mind, that the number of extra cases as a consequence of smoking still is great, since periodontal disease is considered a common disease.

Pathogenisis

Current opinion of the pathogenisis of periodontal disease is that a small group of bacteria are mainly responsible for the initiation and progression of disease and that bacterial activation of host defence mechanisms result in tissue destruction (^{Taichman and Lindhe, 1989} ; ^{Williams, 1990} ; ^{Socransky and Haffajee, 1991} ; ^{Page and Kornman, 1997}). Tobacco smoking might interact both with the microflora and the host response.

Tobacco smoking and periodontal microflora

Many epidemiological and clinical studies have observed smokers to harbour more plaque and calculus than non-smokers (^{Arno et al., 1958} ; ^{Kristoffersen, 1970} ; ^{Alexender, 1970} ; ^{Ainamo, 1971} ; ^{Sheiham, 1971} ; ^{Preber and Kant, 1973} ; ^{Lavstedt, 1975} ; ^{Preber and coll., 1980} ; ^{Feldman et al., 1983} ; ^{Ismail et al., 1983} ; ^{MacGregor, 1984}). These observations have supported the deletorious effects of tobacco-smoking on the periodontal tissues to be of an indirect origin, i.e. depending on a heavier amount of plaque in the smokers. However clinical studies have reported a similar plaque accumulation rate in smokers and non-smokers (^{Bastian and Waite, 1978} ; ^{Swenson, 1979} ; ^{Bergström, 1981} ; ^{Bergström and Preber, 1986}), thereby suggesting smokers´ greater amount of plaque depending of an inferior oral hygiene (^{MacGregor, 1984}).

Currently periodontal diseases are looked upon as basically specific infections (^{Slots et al., 1986} ; ^{Slots et Listgarten, 1988}). Human periodontitis is initiated and perpetuated by a small group of predominantly anaerobic, gramnegativ bacteria that colonize the subgingival area (^{Page and Kornman, 1997}). In accordance smoking might be expected to exert its effects by promoting such infections. In a recent study (^{Preber et al., 1992}), the interrelationships between smoking and some anaerobic periopathogens were described in a sample of patients with severe periodontitis. No differences were found between smokers and non-smokers regarding the occurrence, relative frequency or various combinations of A. actinomycetemcomitans, P. gingivalis and P. intermedia. The results have been confirmed in other studies (^{Stoltenberg et al., 1993} ; ^{Preber et al., 1995}).

However, in another recent study (^{Zambon et al., 1996}) including a sample of 1 400 subjects from a general population, microbiological analysis demonstrated that smokers harbored significantly higher levels of B. forsythus than non-smokers.

Tobacco smoking and host response

Since smoking does not appear to have any major effect on the periodontal bacterial flora, it appears more likely that smoking might influence the periodontal host response.

Smoking has important effects on the immune system. Smokers have demonstrated decreased immunoglobulin levels of IgG, IgA and IgM, but increased levels of IgE (^{Holt and Keast, 1977} ; ^{Gerrard et al., 1980} ; ^{Johnson et al., 1990}). Lower T-suppressor CD8 lymphocyte cell counts and higher counts of other lymphocytes have been reported for smokers (^{Mili et al., 1991}). Lymphocyte DNA adducts have been reported higher for smokers (^{Savela and Hemminki, 1991}).

It is also well known that smoking impairs the functions of the oral neutrophils. Both the viability, chemotaxis and phagocytosis are influenced (^{Eichel et Sharick, 1969} ; ^{Thomas et al., 1973} ; ^{Kenney et al., 1977} ; ^{Hughes et al., 1985} ; ^{Mac Farlane, 1992}).

The pro-inflammatory cytokines IL-1 and TNF-alfa are considered key regulators of the host response to microbial infection. Recently a specific periodontitis associated IL-1 genotype was reported (^{Kornman et al., 1997}), which was correlated with high levels of IL-1 production in non-smokers. However in smokers, severe disease was not correlated with the genotype, which indicates that the genetic association was evident only when smokers were excluded. This finding further confirms the importance of smoking as a risk factor for periodontitis. In another recent study (^{Boström et al., 1998}) smokers demonstrated higher levels of TNF-alfa in a 5 year-follow up study after periodontal surgery, which might indicate TNF-alfa as a marker for impaired healing in smokers.

Mechanisms

The exact mechanisms by which cigarette smoking influences the periodontal tissues are not known. Besides possible specific effects from periopathogenic bacteria and by immunosuppression, there might be cytotoxic effects from nicotine on the fibroblast function. As with other tissues responses, a normal fibroblast function is critical for the maintenance of periodontal tissues and for optimal wound healing. It has been reported that nicotine can be stored and released from periodontal fibroblasts (^{Hanes et al., 1991}) and that nicotine inhibits the growth of gingival fibroblasts and their production of fibronectin and collagen (^{Tipton and Dabbous 1995}). However, it remains unclear whether these nicotine loaded cells attach better (^{Peacock et al., 1993}) or worse (^{Raulin et al., 1989}) to different surfaces. Presumabily, these in vitro findings on the effects of nicotine on the fibroblast function may also occur in vivo, and thereby also influence the healing potential of the periodontium.

Tobacco smoking and periodontal therapy

Tobacco smoking has often been cited as an important contributing factor for poor wound healing and postoperative complications following surgical interventions (^{Mosely et Finseth, 1977} ; ^{Rees et al., 1984} ; ^{Nolan et al., 1985}). Smoking has also detrimental effect on implants survival (^{Bain and Moy, 1993} ; ^{Gorman et al., 1994}).

Cigarette smoking seems to adversely influence the outcome of various modalities of periodontal therapy. Concerning non-surgical periodontal therapy including scaling and rootplaning, there are only short-term studies available evaluating the results from 1 to 3 months after active treatment. However, in spite of a comparatively short period of healing the result was inferior for smokers in all studies. Probing depths reductions in the maxillary anterior region were reported significantly lower in smokers as compared to non-smokers already 1 month after treatment (^{Preber and Bergström, 1985a}). In a subsequent study, gingival bleeding on probing was significantly less reduced in smokers at the same time of observation (^{Preber and Bergström, 1985b}). With an observation period extended to 2 months, the differences in probing depth reduction were still greater (^{Preber et al., 1995}). The number of diseased sites was reduced by 40 % in smokers as against 57 % in non-smokers, although there were no differences in the composition of subgingival flora (A. actinomycetemcomitans, P. gingivalis, P. intermedia) either before or after treatment between the smoking groups. In a recent study (^{Kinane and Radvar, 1997}) with an observation period of 6 weeks, 3 locally delivered antimicrobial systems as adjuncts to scaling and rootplaning was compared between smokers and non-smokers. The improvement in both probing depths and attachment levels was significantly greater in the non-smoker patients. ^{Grossi et al. (1995}) in a study comprising 1 400 subjects from a general population further confirmed the results with the observation period extended to 3 months, displaying an inferior pocket reduction and attachment level gain for smokers. However concerning the subgingival microflora more smokers than non-smokers were positive for P. gingivalis and B. forsythus after treatment.

Concerning periodontal surgical therapy, in a 12 month follow-up study, the probing depth reduction was significantly less for smokers compared to non-smokers, 0.8 and 1.3 mm respectively (^{Preber and Bergström, 1990}).

In 2 recent long-term studies, the treatment results following 4 different treatment modalities, surgical as well as nonsurgical, were evaluated after 6 and 7 years respectively (^{Ah et al., 1994} ; ^{Kaldahl et al., 1996}). The outcome of therapy was significant inferior for smokers concerning pocket depth reduction and clinical attachment gain for the entire observation period. There was also a trend towards a dose-response relation, indicating an inferior outcome for heavy smokers as compared to light smokers, and for light smokers as compared to non-smokers or past smokers. ^Boström ) in another long term study, 5 years after periodontal surgery, not only confirmed earlier observations on inferior pocket reductions in heavy smokers but also reported on significant differences in radiographic bone gain. Smokers did not exhibit any gain in periodontal bone height as contrasted to both non-smokers and past smokers who displayed significant gains over time.

Results from studies on periodontal regenerative surgery suggest that smoking also adversely affects this kind of surgical treatment outcome. Both guided tissue regeneration procedures, regenerative procedures using bonegrafts and soft tissue graft procedures report significantly inferior outcome for smokers (^{Miller, 1987} ; ^{Tonetti et al., 1995} ; ^{Rosen et al., 1996} ; ^{Trombelli and Scabbia, 1997}).

Refractory periodontitis

It is well known that some patients do not respond as expected to the best of periodontal therapy. These non-responders or " down-hill " patients exhibiting continuing attachment loss after treatment are usually classified as refractory periodontitis cases. Although many clinicans have experienced an excess number of smokers in this category, up to now only few studies have considered the influence of smoking in refractory periodontitis. However recent studies have shown a heavy overrepresentation of smokers among refractory cases (^{MacFarlane et al., 1992} ; ^{Bergström and Blomlöf, 1992}).

Smoking cessation

At present there are no studies reporting the effects of smoking cessation on periodontitis patients. However both the prevalence and the severity of periodontitis is greater in current smokers as compared to former smokers as compared to non-smokers (^{Bergström et al., 1991} ; ^{Dunford et al., 1991} ; ^{Haber et al., 1993} ; ^{Grossi et al., 1994} ; ^{Grossi et al., 1995} ; ^{Haber and Kent, 1992}). ^Bolin ) have reported on the effect of changed smoking habits on marginal bone loss. In a longitudinal study 349 individuals were examined in 1970 and in 1980 respectively concerning radiographic marginal bone loss. 44 subjects gave upp smoking during this 10-year period, showing significantly less bone loss, as compared to those 139 who smoked regularly during the period.

Extrapolation of the results from these studies would suggest smoking cessation as an important factor of periodontal therapy. However clinical studies with smoking cessation groups are needed to further substantiate these results.

Smokeless tobacco and periodontal health

Smokeless tobacco products, such as snuff and chewing tobacco, and their effects on the periodontal tissues have not been as extensively studied as tobacco smoking and periodontal disease. Furthermore, published clinical studies on smokeless tobacco, are usually performed on young subjects, implying a comparatively short period of tobacco consumption. Smokeless tobacco and snuff have long been associated with local gingival recession and oral leukoplakia (^{Weintrab and Burt, 1987} ; ^{Robertson et al., 1990} ; ^{Wray and McGuirt, 1993}). In a recent case-control study, smokeless tobacco users reported increased gingival index scores and elevated prostaglandin E2 levels in gingival crevicular fluid at placement sites of snuff (^{Johnsson et al., 1996}). This might indicate tobacco induced synthesis of prostaglandin E2, which might play a role for tobacco related oral disease.

However data are currently insufficient to support an association between the use of smokeless tobacco and generalized or severe periodontal disease.

Summary and conclusions

Epidemiological and clinical studies strongly supports the concept of tobacco smoking as a major risk factor for periodontal disease. Attributable risk estimates have calculated a considerable over risk for smokers. Accordingly cigarette smoking affects the prevalence and severity of adult periodontitis, refractary periodontitis and ANUG. In studies where plaque levels have been adjusted for, smokers have reported greater probing depths, attachment levels and radiographic marginal bone loss, indicating an independent effect of smoking. Smoking exerts a suppressed and masking effect on gingival symptoms of inflammation. At present no studies support an association between smokeless tobacco and generalized periodontitis. However gingival recession may occur at sites of placement. Clinical studies have also demonstrated that smoking adversely affects the outcome of different kinds of periodontal therapy.

Published studies on periodontitis patients have not demonstrated any major differences of the periodontal microflora in smokers compared to non-smokers. Smoking may affect various forms of the immune response system. Several studies have shown a dose-response relation between the severity of periodontal disease and the amount of smoking. Although, there are no studies at present on the effect of smoking cessation, results from recent clinical and epidemiological studies strongly suggest that smoking cessation may beneficially influence periodontal disease progression and improve results of periodontal therapy.

BIBLIOGRAPHY

• AH MKB, JOHNSON KB, KALDAHL WB, PATIL KD, KALKWARF KL. The effect of smoking on the response to periodontal therapy. J Clin Periodontol 1994;21:91-97.
• AINAMO J. The seeming effect of tobaccoconsumption on the occurence of periodontal disease and dental caries. Suom Hamm Lääk Toimit 1971;67:87-94.
• ALEXANDER AG. The relationship between tobacco, smoking, calculus ant plaque accumulation and gingivitis. Dental Health 1970;9:6-9.
• ARNO A, WAERHAUG J, LOVDAL A, SHEI O. Incidence of gingivitis as related to sex, occupation tobacco consumption, toothbrushing and age. Oral Surg 1958;11:587-595.
• BAIN CA, MOY PK. The association between the failure of dental implants and cigarette smoking. Int J Oral Maxillofac Implants 1993;8:609-615.
• BARTECCHI CD, MACKENZIE TD, SCHRIER RW. The human costs of tobacco use. N Engl J Med 1994;331:907-912.
• BASTIAN RJ, WAITE JM. Effects of tobacco smoking on plaque development and gingivitis. J Periodontol 1978;49:480-482.
• BERGERON EF. De la stomatie ulcéreuse des soldats. Paris : Labe, 1859 ; p. 70.
• BERGSTRÖM J. Short-term investigation on the influence of cigarette smoking upon plaque accumulation. Scand J Dent Res 1981;89:235-238.
• BERGSTRÖM J. Cigarette smoking as a risk factor in chronic periodontal disease. Comm Dent Oral Epidemiol 1989;17:245-247.
• BERGSTRÖM J. Oral hygiene compliance and gingivitis expression in cigarette smokers. Scand J Dent Res 1991;98:497-503.
• BERGSTRÖM J, BLOMLÖF L. Tobacco smoking major risk factor associated with refractory periodontal disease. J Dent Res 1992;71:297.
• BERGSTRÖM J, ELIASSON S. Cigarette smoking and alveolar bone height in subjects with a high standard of oral hygiene. J Clin Periodontol 1987;14:466-469.
• BERGSTRÖM J, ELIASSON S. Noxious effect of cigarette smoking on periodotal health. J Periodont Res 1991;62:242-246.
• BERGSTRÖM J, ELIASSON S, PREBER H. Cigarette smoking and periodontal bone loss. J Periodontol 1991;62:242-246.
• BERGSTRÖM J, FLODERUS-MYRHED B. Co-twin control study of the relationship between smoking and some periodontal disease factors. Comm Dent Oral Epidemiol 1983;11:113-116.
• BERGSTRÖM J, PERSSON L, PREBER H. Influence of cigarette smoking on vascular reaction during experimental gingivitis. Scand J Dent Res 1988;96:34-39.
• BERGSTRÖM J, PREBER H. The influence of cigarette smoking on the development of experimental gingivitis. J Periodont Res 1986;21:668-676.
• BERGSTRÖM J, PREBER H. Tobacco use as a risk factor. J Periodontol 1994;65:545-550.
• BOLIN A, EKLUND G, FRITHIOF L, LAVSTEDT S. The effect of changed smoking habits on marginal alveolar bone loss. Swed Dent J 1993;17:211-216.
• BOSTRÖM L, LINDER LE, BERGSTRÖM J. Influence of smoking on the outcome of periodontal surgery. A 5-year follow-up. J Clin Periodontol 1998;25:194-201.
• DANIELSEN B, MANJI F, NAGELKERKE N, FEJERSKOV O, BAELUM V. Effect of cigarette smoking on the transition dynamics in experimental gingivitis. J Clin Periodontol 1991;17:159-164.
• DUNFORD RG, LYON E, HO AW. Smoking as a significant risk factor for severe adult periodontitis. J Dent Res 1991;70:590.
• EICHEL B, SHARICK HA. Tobacco smoke toxicity. Loss of human oral leukocyte function and fluid cell metabolism. Science 1969;166:1424-1428.
• FELDMAN RS, BRAVACOS JS, ROSE CL. Association between smoking different tobacco products and periodontal disease indexes. J Periodontol 1983;54:481-487.
• FELDMAN RS, ALMAN JE, CHAUNCEY HH. Periodontal disease indexes and tobacco smoking in healthy aging men. Gerodontics 1987;1:43.
• GERRARD JW, HEINER DC, MINK J, MEYERS AL, DOSMAN JA. Immunoglobulin levels in smokers and non-smokers. Ann Allergy 1980;44:261.
• GOLDHABER P, GIDDON DB. Present concepts concerning the aetiology and treatment of acute necrotizing ulcerative gingivitis. Int Dent J 1964;14:468-496.
• GORMAN LM, LAMBERT PM, MORRIS HF, WINKLER S. The effect of smoking on implant survival at second-stage surgery. Impl Dent 1994;3:165-168.
• GROSSI SG, ZAMBON JJ, HO AW, GENCO RJ. Assessment of risk for periodontal disease. I. Risk indicators for attachment loss. J Periodontol 1994;65:260-267.
• GROSSI SG, GENCO RJ, MACHTEI EE. Assessment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol 1995;66:23-29.
• GOULTSCHIN J, SGAN COHEN HD, DONCHIN M, BRAYER L, SOSKOLNE WA. Association of smoking with periodontal treatment needs. J Periodontol 1990;61:364-367.
• HABER J, KENT RL. Cigarette smoking in a periodontal practice. J Periodontol 1992;63:100-106.
• HABER J, WATTLES J, CROWBY M, MANDELL R, KAUNUDI J, KENT RL. Evidence for cigarette smoking as a major risk factor for periodontitis. J Periodontol 1993;64:16-23.
• HANES PJ, SCHUSTER GS, LUBAS S. Binding, uptake, and release of nicotine by human gingival fibroblasts. J Periodontol 1991;62:147-152.
• HOLT PG, KEAST D. Environmentally induced changes in immunological function : acute and chronic effects of inhalation of tobacco smoke and other atmospheric contaminants in man and experimental animals.
• HUGHES DA, HASLAM PL, TOWNSEND PJ, TURNER-WARWICK M. Numerical and functional alterations in circulatory lymphocytes in cigarette smokers. Clin Exp Immunol 1985;61:459-466.
• ISMAIL AI, BURT BA, EKLUND SA. Epidemiologic patterns of smoking and periodontal disease in the United States. J Am Dent Assoc 1983;106:617-621.
• ISMAIL AI, MORRISON EC, BURT BA, CAFFESSE RG, KAVANAGH MT. Natural history of periodontal disease in adults : Findings from the Tecumseh periodotal disease study, 1958-87. J Dent Res 1990;69:430.
• JOHNSON JD, HOUCHENS DP, KLUWE WM, CRAIG DK, FISHER GU. Effects of mainstream and environmental tobacco smoke on the immune system in animals and humans. A review. Critic Rev Toxicology 1990;20:369.
• JOHNSON GK, POORE TK, PAYNE JB, ORGAN CC. Effect of smokeless tobacco extract on human gingival keratinocyte levels of prostaglandin E2 and interleukin-1. J Periodontol 1996;67:116-124.
• KALDAHL WB, JOHNSON GK, PATIL KD, KALKWARF KL. Levels of cigarette consumption and response to periodontal therapy. J Periodontol 1996;67:675.
• KARDACHI BJR, CLARKE NG. Aetiology of acute necrotizing gingivitis : a hypothetical explanation. J Periodontol 1974;45:830-832.
• KENNEY EB, KRAAL JH, SAXE SR, JONES J. The effect of cigarette smoke on human oral polymorphonuclear leukocytes. J Periodontol Res 1977;12:227-234.
• KINANE DF, RADVAR M. The effect of smoking on mechanical and antimicrobial periodontal therapy. J Periodontol 1997;68:467-472.
• KORNMAN KS, CRANE A, WANG HY, DI GIOVINE FS, NEWMAN MG, PIRK FW, WILSON Jr TG, HIGGINBOTTOM FL, DUFF GW. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997;24:72-77.
• KRISTOFFERSEN T. Periodontal conditions in Norwegian soldiers - an epidemiological and experimental study. Scan J Dent Res 1970;78:34-53.
• LAVSTEDT S. A methodological-roentgenological investigation on marginal alveolar bone loss. Acta Odontol Scand 1975;33: suppl. 67.
• LINDEN GJ, MULLALLY BH. Cigarette smoking and periodontal destruction in young adults. J Periodontol 1994;65:718-723.
• LUDWICK W, MASSLER M. Relation of dental caries experience and gingivitis to cigarette smoking in males 17 to 21 years old. J Dent Res 1952;31:319-322.
• MACFARLANE G, HERZBERG M, WOLF L, HARDIE N. Refractory periodontitis associated with abnormal polymorphonuclear leukocyte phagocytosis and cigarette smoking. J Periodontol 1992;63:908-913.
• MACGREGOR IDM. Toothbrushing efficiency in smokers and non-smokers. J Clin Periodontol 1984;11:313-320.
• MACGREGOR IDM, RUGG-GUNN AJ. Uninstructed toothbrushing behaviour in young adults in relation to cigarette smoking in Newcastle. Comm Dent Oral Epidemiol 1984;12:358-360.
• MARTINEZ-CANUT PLA, LORCA A, MAGÀN R. Smoking and periodontal disease severity. J Clin Periodontol 1995;22:743-749.
• MILI F, FLANDERS W, BORING J, ANNEST J, DESTEFANO F. The association of race, cigarette smoking, and smoking cessation to measures of the immune system in middle-aged men. Clin Immunol Immunolpathol 1991;59:187-200.
• MILLER PD. Root coverage with free gingival grafts. Factors associated with incomplete coverage. J Periodontol 1987;58:674-681.
• MOSELY LH, FINSETH F. Cigarette smoking : Impairment of digital blood flow an wound healing in the hand. The Hand 1977;9:97-101.
• MULLALLY BH, LINDEN GJ. Molar furcation involvement associated with cigarette smoking in periodontal referrals. J Clin Periodontol 1996;23:658-661.
• NOLAN J, JENKINS RA, KURIHARA K, SCHULTZ RC. The acute effects of cigarette smoke exposure on experimental skin flaps. Plast Reconstr Surg 1985;75:544-549.
• PAGE RC, KORNMAN KS. The pathogenesis of human periodontitis : an introduction. Periodontology 2000 1997;14:9-11.
• PEACOCK ME, SUTHERLAND DE, SCHUSTER GS. The effect of nicotine on reproduction and attachment of human gingival fibroblasts in vitro. J Periodontol 1993;64:658-665.
• PINDBORG JJ. Tobacco and gingivitis. J Dent Res 1947;26:261-264.
• POORE TK, JOHNSON GK, REINHARDT RA, ORGAN CC. The effect of smokeless tobacco on clinical parameters of inflammation and gingival crevicular fluid prostaglandin E2, interleukin-1 alpha, and interleukin-1 beta. J Periodontol 1995;66:177-183.
• PREBER H, BERGSTRÖM J. The effect of non-surgical treatment on periodontal pockets in smokers and non-smokers. J Clin Periodontol 1985a;13:319-323.
• PREBER H, BERGSTRÖM J. Occurence of gingival bleeding in smoker and non-smoker patients. Acta Odontol Scand 1985b;43:315-320.
• PREBER H, BERGSTRÖM J. Cigarette smoking in patients referred for periodontal treatment. Scand J Dent Res 1986;94:102-108.
• PREBER H, BERGSTRÖM J. Effect of tobacco smoking on periodontal healing following surgical therapy. J Clin Periodontol 1990;17:324-328.
• PREBER H, KANT T, BERGSTRÖM J. Cigarette smoking, oral hygiene, and periodontal health in Swedish army conscripts. J Clin Periodontol 1980;7:106-113.
• PREBER H, KANT T. Effect of tobacco smoking on periodontal tissue of 15-year-old school children. J Periodontol Res 1973;8:278-283.
• PREBER H, BERGSTRÖM J, LINDER LE. Occurence of periopathogens in smoker and non-smoker patients. J Clin Periodontol 1992;19:667-671.
• PREBER H, LINDER L, BERGSTRÖM J. Periodontal healing and periopathogenic microflora in smokers and non-smokers. J Clin Periodontol 1995;22:946-952.
• RAULIN LA, MCPHERSON JC, McQUADE MJ, HANSON BS. The effect of nicotine on the attachment of human fibroblasts to glass and human root surfaces in vitro. J Periodontol 1989;59:318-325.
• REES TD, LIVERETT DM, GUY CL. The effect of cigarette smoking on skin-flap survival in the face lift patient. Plast Reconstr Surg 1984;73:911-915.
• ROBERTSON PB, WALSH M, GREENE J, ERNSTER V, GRADY D, HAUCK W. Periodontal effects associated with the use of smokeless tobacco. J Periodontol 1990;61:438-443.
• ROSEN PS, MARKS MH, REYNOLDS MA. Influence of smoking on long-term clinical results of intrabony defects treated with regenerative therapy. J Periodontol 1996;67:1159-1163.
• SALVI GE, LAWRENCE HP, OFFENBACHER S, BECK JD. Influence of risk factors on the pathogenesis of periodontitis. Periodontology 2000 1997;14:173-202.
• SAVELA K, HEMMINKI K. DNA adducts in lymphocytes and granulocytes of smokers and non-smokers detected by the 32P-postlabelling assay. Carcinogenesis 1991;12:503-508.
• SCHENKEIN HA, GUNSOLLEY JC, KOERTGE TE, SCHENKIN J, TEW JG. Smoking and its effects on early-onset periodontitis. J Am Dent Assoc 1995;126:1107-1113.
• SHEIHAM A. Periodontal disease and oral cleanliness in tobacco smokers. J Periodontol 1971;42:259-263.
• SLOTS J, BRAGD L, WIKSTRÖM M, DAHLE'N G. The occurence of A. actinomycetemcomitans, B. gingivalis and B. intermedius in destructive periodontal disease in adults. J Clin Periodontol 1986;13:570-577.
• SLOTS J, LISTGARTEN MA. Bacteroides gingivalis, Bacteroides intermedius and actinobacillus actinomycetemcomitans in human periodontal diseases. J Clin Periodontol 1988;15:85-93.
• SOCRANSKY SS, HAFFAJEE AK. Microbial mechanisms in the pathogenesis of destructive periodontal diseases : a critical assessment. J Periodontol Res 1991;26:195-212.
• SOLOMON HA, PRIORE RL, BROSS IDJ. Cigarette smoking and periodontal disease. J Am Dent Assoc 1968;77:1081-1084.
• STAMMERS A. Vincent's infection : observations and conclusions regarding the aetiology and treatment of 1 017 civilian cases. British Dent J 1994;76:147-155.
• STOLTENBERG JL, OSBORNE JB, PIHLSTROM BL, HERTZBERG MC, AEPPLI DM, WOLFF LF, FISHER GE. Association between cigarette smoking, bacterial pathogens and periodontal status. J Periodontol 1993;64:1225-1230.
• SUMMERS CJ, OBERMAN A. Association of oral disease with 12 selected variables. J Dent Res 1968;47:457-462.
• SUTER TW, BUZZI R, BÄTTIG K. Cardiovascular effects of smoking cigarettes with different nicotine deliveries. A study using multilead plethysmography. Psychopharmacology 1983;80:106-112.
• SWANGO PA, KLEINMAN DV, KONZELMAN JL. HIV and periodontal health : A study of military personnel with HIV. J Am Dent Ass 1991;122:49-54.
• SWENSON HM. The effects of tobacco smoking on plaque formation. J Periodontol 1979;50:146-147.
• TAICHMAN N, LINDHE J. Pathogenesis of plaque-associated periodontal disease. In : Textbook of clinical periodontology. LINDHE J, ed. Copenhagen : Munksgaard, 1989 ; pp.153-192.
  The research, Science and Therapy Commitee of the American Academy of Periodontology. Position paper. Tobacco use and the periodontal patient. J Periodontol 1996;67:51-56.
• THOMAS W, HOLT PG, KEAST D. Effect of cigarette smoking on primary and secondary humoral responses in mice. Nature 1973;243:240.
• TIPTON DA, DABBOUS MK. Effects of nicotine on proliferation and extracellular matrix production of human gingival fibroblasts in vitro. J Periodontol 1995;66:1056-1064.
• TONETTI MS, PINO PRATI GP, CORTELLINI P. Effect of cigarette smoking on periodontal healing following GTR in intrabony defects. A preliminary retrospective study. J Clin Periodontol 1995;22:229-234.
• TROMBELLI L, SCABBIA A. Healing response of gingival recession defects following guided tissue regeneration in smokers and non-smokers. J Clin Periodontol 1997;24:529-533.
• US Department of Health, Education and Welfare. Smoking and Health. A report of the surgeon general. Washington. DHEW Publication No (PHS) 79-50066. 1979, chapter 4:651-66.
• US Department of Health and Human Services. The Health Consequences of Smoking. Cancer. A report of the surgeon general. Washington. DHHS (PHS) 82-50179. 1982, 21-63.
• WEINTRAUB JA, BURT BA. Periodontal effects and dental caries associated with smokeless tobacco use. Public Health Rep 1987;102:30-35.
• WILLIAMS RC. Periodontal disease. New Engl J Medic 1990;322:373-382.
• WRAY A, McGUIRT F. Smokeless tobacco usage associated with oral carcinoma. Incidence, treatment, outcome. Arch Otolaryngol Head Neck Surg 1993;119:929-933.
• ZAMBON JJ, GROSSI SG, MACHTEI EE, HO AW, DUNFORD F, GENCO RJ. Cigarette smoking increases the risk for subgingival infection with periodontal pathogens. J Periodontol 1996;67:1050-1054.