Refractory Periodontitis Associated With Abnormal Polymorphonuclear Leucocyte Phagocytosis

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Current Concepts in Diagnosis and Treatment of Periodontitis Ingvar Magnusson andJan Lindhe This article describes some areas of periodontal research and current opinions regarding detection of disease progression, as well as risk indicators and risk factors associated with disease progression. Longitudinal probing of periodontal attachment level is considered the gold standard for detection of disease activity although there are problems with this concept. Digital subtraction radiography can assist in the detection of minor changes of alveolar bone height and density. Risk factors such as composition of subgingival plaque and gingival crevicular fluid, as well as the effect of smoking are discussed. Adjunctive treatment with both antibiotics and nonsteroidal anti-inflammatory drugs, systemic or local, seems to be helpful in some forms of disease, Immunization to prevent colonization of tooth surfaces and pockets by periodontal pathogens does not seem to be feasible in the near future. (Semin Orthod 1996;2:13-20.) Copyright © 1996 by W.B. Saunders Company

ongitudinal probing of periodontal attachm e n t has b e e n and still is the gold standard for the diagnosis of active disease or progression of disease. Interesting questions arise: How reproducible and exact are the measurements? Which measured differences are clinically significant? Efforts have focused on the i m p r o v e m e n t of probing validity for earlier detection of disease progression. Gibbs et al 1 developed the Florida Probe system (Florida Probe Corporation, Gainesville, FL) that combines the advantages of constant probing force with precise electronic meas u r e m e n t and c o m p u t e r storage of the data. T h e Florida Probe eliminates the potential errors associated with visual reading. T h e system, which consists of a p r o b e handpiece, a digital readout, a foot switch, c o m p u t e r interface, and computer, was studied by Magnusson et al z and correlated to standard p r o b e measurements. It was con-

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From the Department of Oral Biology, College of Dentistry, University of Flarida, Gainesville, bL; and the Department of Periodontology, Faculty of Odontology, University of G6teborg, G6teborg, Sweden. Address correspondenceto Ingvar Magnusson, DDS, OdontDr, Department of Oral Biology, College of Dentistry, University of Florida, Gainesville,FL 32610-0275. Copyright© 1996 by W.B. Saunders Company 1073-8746/96/0201-000355.00/0

cluded that the reproducibility of pocket d e p t h measurements obtained with the electronic probe was superior to the reproducibility of those obtained with a standard probe. T h e r e was no difference in time c o n s u m p t i o n between the two methods; however, p r o b i n g data f r o m the electronic p r o b e are entered into the c o m p u t e r automatically, eliminating the n e e d for an assistant to record the measurements. A slightly different electronic p r o b e using an optical encoder transduction e l e m e n t (Interprobe, Bausch & Lomb, Tucker, GA) was c o m p a r e d with conventional probing. 3 Reproducibility was somewhat higher with the I n t e r p r o b e c o m p a r e d with conventional probing. To detect progression of periodontal disease for a short period, Haffajee et al 4 r e c o m m e n d e d the tolerance method, in which the difference between replicate a t t a c h m e n t level measurements is used to calculate a standard deviation for all the m e a s u r e m e n t pairs m a d e in one individual. The subject threshold for a t t a c h m e n t loss in an individual site is defined as three standard deviations of the m e a n differences between all the paired measurements. For 22 subjects, s t a n d a r d deviation values varied f r o m +0.52 to 1.30 ram, resulting in a m e a n subject threshold for detection of a t t a c h m e n t

Seminars in Orthodontics, Vol 2, No 1 (March), 1996: pp 13-20

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loss of 2.46 m m (range: 1.56 to 3.90 mm), indicating that in some patients a considerable loss of attachment is n e e d e d to determine progression of disease with a high level of probability. Magnusson et aP also investigated the reproducibility of attachment level measurements using the Florida Probe. With the use of fixed reference points on custom-made acrylic stents, a high level of agreement was achieved for attachment level measurements made by different examiners (mean SD = +_0.28 mm) or by a single examiner during different visits (mean SD = +-0.33 mm). The highest agreement between a t t a c h m e n t level m e a s u r e m e n t s was achieved when the measurements were perf o r m e d at the same visit, even t h o u g h the measurements were performed by two different examiners. It is significant that by using the tolerance method, Magnusson et al 5 established that the Florida Probe was more sensitive in detecting a true attachment loss than was the standard periodontal probe. For the 10 subjects, the SD varied from +-0.25 to 0.33 mm, with an average of +_0.28 mm. With the standard manual probe, Haffajee et al 4 reported an average of -+0.82 mm, with a range of -+0.52 to 1.30 mm. Using three SD as a threshold for attachment loss, the average threshold in the Magnusson study 5 would be 0.84 ram, compared with 2.46 m m tor Haffajee 4 et al. Thus, it seems that progressive periodontal disease could be detected earlier by the constantforce electronic probe. Several reports indicate that measurements of deeper pockets are difficult. 6+ In the study by Haffajee et al 4 subjects were classified as having advanced periodontal disease; the Magnusson study 5 dealt with subjects having minimal-to-early disease. However, when the Florida Probe was used in subjects with severe periodontal disease, the SD was f o u n d to be of the same magnitude or lower in that group of subjects. Yang et al 1° studied different probing designs to investigate the reproducibility of the Florida Probe. The maximum probing error was found to be approximately +_0.3 mm, which is considerably smaller than that f o u n d in most previous studies. The errors associated with the periodontal condition and probing effect were also estimated. The variance c o m p o n e n t s obtained here can be used for determining the sample size in controlled clinical studies.

Jeffcoat et a111 have designed an electronic periodontal probe that can automatically detect the cemento-enameljunction. TheJeffcoat probe provided highly reproducible measurements in 10 h u m a n subjects with attachment loss ranging between 0.5 and 7.5 m m who were measured 10 times for 2 weeks. ~2 The overall mean SD of the repeated measurements was + 0.17 ram. Two other electronic probes, the Toronto Probe 13 and the Florida Disk Probe 14 have been designed to measure changes in attachment level using the occlusal surface or the incisal edge as a reference point. The Toronto Probe works on constant air pressure and measures attachment level from the occlusal surface. In a study of duplicate measurements in nine subjects, it was f o u n d that 82% of the measurements were within 1 m m difference. The SD for all teeth was +_0.46. The Florida Disk Probe was used independently by Low et aP 4 and Osborn et a115 to assess reproducibility of repeated measurements. Both studies resulted in highly reproducible measurements with low standard deviations between replicate m e a s u r e m e n t s (mean SD = +0.26 and +0.18 m m respectively). This probe does not require a prefabricated stent. Gerlach et a116 described repeatability of controlled pressure relative attachment level measurements collected in a multicenter clinical trial setting. Relative attachment level measurements were recorded for 213 patients by five different examiners at three study centers. For each patient, measurements were recorded from four periodontally involved posterior teeth. Duplicate attachment level measurements were collected at baseline, and after 3 and 6 months from each selected site. A total of 2,453 duplicate measurements were collected during the study. O f these, 215 (8.8%) pairs differed by more than 1.0 mm. Overall, the mean SD of replicate measurements was -+0.29 mm. The repeatability shown in this study supports use of controlled pressure probing to evaluate changes in periodontitis in multicenter studies. Electronic probes seem to be superior to manual probes. In the studies described previously, the range of overall SD for repeated measurements of individual sites in different subjects was +_0.17 to +_0.32 ram. Regarding the ability to detect significant attachment level changes, this is an improvement over earlier findings.

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Probing a t t a c h m e n t level is currently the gold standard for detecting active disease at a site, but changes in a t t a c h m e n t level are not always easy to interpret because of the limitation of p r o b i n g in assessing the histological a t t a c h m e n t level. Short-time changes, both loss and gain, may only reflect fluctuation in collagen content accompanied by changes in inflammatory status and may not indicate real a t t a c h m e n t changes. Watts 17 suggested that it is also possible that despite o u r best efforts, these changes might also represent errors in p r o b e p l a c e m e n t or angulation. If a t t a c h m e n t loss is confirmed at a later time, however, it probably represents a true loss, indicative of active and progressive periodontal disease.

tion radiography is higher than that previously r e p o r t e d using periodontal probing, and that the p r o p o r t i o n of sites losing b o n e is greater than the p r o p o r t i o n gaining bone. However, the clinical significance of a change in b o n e density is not clear. We must keep in m i n d that changes in alveolar b o n e may not correlate with changes in the true a t t a c h m e n t level or with measurements of the clinical a t t a c h m e n t level. Nonetheless, in a periodontal patient, sites that show evidence of b o n e loss must be considered to have been active sites at some time during the time interval the radiographs were taken, especially when they correlate with loss of attachment.

Computer-assisted Subtraction Radiography

Overwhelming data support the role of specific bacteria in the cause of periodontal diseases. A classical association is the one between localized juvenile periodontitis and ActinobaciUus actinomycetemcomitans.24-'~° Several other potential periodontal pathogens have b e e n described primarily in association with adult chronic periodontal disease. Species of note include mainly gramnegative anaerobic bacteria: Bacteroidesforsythus, Campylobacter rectus, Eubacterium spp, EikeneUa

Over the past years the technique of subtraction radiography has been refined. More sensitive a n d objective m e t h o d s for analyzing radiographs 1~21 and perhaps a better opportunity to c o m p a r e changes in a t t a c h m e n t with changes in b o n e density are offered. H a u s m a n n et al zl m o n i t o r e d crestal interdental b o n e in 15 untreated patients with periodontitis for a 6-month period. Nine percent of the sites exhibited b o n e loss, whereas 4% exhibited b o n e gain. T h e investigators suggested that the findings were consistent with the theory of exacerbation and remission at crestal alveolar b o n e sites in untreated periodontitis patients. However, in this study there was no attempt to correlate the findings to changes in m e a s u r e m e n t s of a t t a c h m e n t level. Few attempts have b e e n m a d e to correlate b o n e loss with changes in attachment. Deas et a122 c o m p a r e d the frequency of a t t a c h m e n t loss in 21 subjects with periodontitis at baseline and at 3, 6, and 9 months. They r e p o r t e d changes in b o n e density in 53% of sites at 3 months, 56% at 6 months, and 62% at 9 months. With 88% to 92% of attachment level measurements reproducible within 1.0 m m , the frequency of a t t a c h m e n t level changes was 19% at 3 months, 25% at 6 months, and 32% at 9 months. Cogen et a123 subtracted radiographs taken at baseline, 3 months, and 6 months and reported that of the sites examined, 23% were losing b o n e and 3% were gaining bone. This suggests that the prevalence of active b o n e loss r e p o r t e d using subtrac-

Microbiology

corrodens, Fusobacterium nucleatum, Peptostreptococcus micros, Porphyromonas gingivalis, Prevotella intermedia, Selenomonas spp and spirochetes have been strongly associated with diseased sites. 3a-3s However, Streptococcus intermedius has also b e e n identified in forms of refractory periodontal d i s e a s e 9 This condition was described by the American Academy of Periodontology as a disease that continues to progress with loss of connective tissue a t t a c h m e n t and bone despite appropriate periodontal therapy. Traditionally, bacteria have b e e n cultured and identified on selective and nonselective m e d i a but also microscopic techniques have b e e n used to identify morphotypes. Recently, DNA probes have been developed to detect the presence of putative pathogens. 4°42 Several of these probes are commercially available and some can be used chair-side for rapid identification. T h e presence of a potential p a t h o g e n must always be regarded as a risk factor and not as a disease indicator. Patients with refractory periodontal disease have often had previous antibiotic therapy resulting in the d e v e l o p m e n t of antibiotic resistance and in these cases it seems

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advisable to base continued antibacterial therapy on microbial susceptibility.

Antimicrobial Approach to the Treatment of Periodontal Diseases Conventional periodontal therapy, including scaling, root planing, and possibly periodontal surgery, is still the therapy of choice and is very successful provided that the patient adheres to a regular maintenance schedule. However, in some forms of disease, antimicrobial therapy is appropriate as an adjunct to conventional therapy (for review4a,44). In patients with adult periodontitis administration of systemic antibiotics without mechanical treatment has shown little promise. The use of systemic tetracycline in the treatm e n t of juvenile periodontitis is well docum e n t e d and has been proven effective in suppressing subgingival A actinomycetemcomitans. 26 In patients with refractory periodontal disease subgingival plaque exhibits a high percentage of microorganisms with resistance, especially against tetracycline. Therefore, Magnusson et aP 9 selected antibiotics, based on susceptibility testing, as an adjunct to treat patients with refractory periodontal disease. The results were considerably better than those obtained in a placebo control group. Recently, research has focused on local antibiotic therapy to achieve a high local drug concentration and to avoid side effects observed with systemic administration. Favorable results have been described with the local delivery of tetracycline (25%) impregnated ethylene vinyl acetate fibers, 45,46 the application of tetracycline (2%) in a lipid gel, 47 and the application of metronidazole (25%) in lipid gel. 4s The use of lower-than-normal doses of tetracycline to treat periodontal disease has been investigated by Rifkin et al. 49 They showed that the treatment was effective in preventing attachment loss in adult periodontitis patients. Low doses of tetracycline effectively inhibit pathologically excessive collagenase activity in gingival tissue. 5°

Gingival Crevicular Fluid Analysis of GCF shows a n u m b e r of enzymes, metabolic byproducts, serum proteins, and other substances related to the inflammatory process, tissue degradation, and cell death. Identification

and quantification of these substances may provide better understanding of both the dynamics and metabolic stages of the periodontal tissues. A n u m b e r of enzymes reflecting tissue remodeling or destruction have been studied. These include collagenase, [3-glucuronidase ([3-G), arylsulfatase (AS), and L-aspartate aminotransferase (AST). Villela et a151 studied collagenolytic activity in crevicular fluid from subjects with chronic adult periodontitis, localized juvenile periodontitis, gingivitis, and from healthy control subjects. Among subjects, collagenase activity increased with severity of disease. Among sites, significant correlation was found between crevicular fluid activity and pocket depth in chronic adult periodontitis and in localized juvenile periodontitis, but not in gingivitis. Birkedal-Hansen et a152 reported that neither gingival crevicular fluid flow nor collagenolytic activity are good indicators or predictors of bone loss. On the other hand, Ciancio et a153suggested that gingival crevicular fluid collagenolytic activity may be of diagnostic value in periodontal disease, however, they did not monitor attachm e n t level changes. It is clear that further investigation is n e e d e d to establish if collagenase levels can be used as indicators of progressive periodontal disease. Lamster et a154 evaluated crevicular fluid for collagenase, [3-G, and AST during development of experimental gingivitis in humans. They found that after 4 weeks the absolute a m o u n t of active collagenase had increased 550% in interproximal areas. For interproximal sites the increase in [3-G activity was 180% and for AS 240%. Thus, these enzyme levels correlated positively with increased gingival inflammation, although increases in specific enzyme levels lagged slightly behind increases in gingival index. H a r p e r et a155 evaluated lysosomal [3-G and AS and cytoplasmic lactate dehydrogenase (LDH) enzyme activity and the composition of subgingival plaque flora in patients with adult periodontitis. [3-G levels correlated significantly with populations of spirochetes, P intermedius, Pgingivalis, and total lactosenegative black-pigmenting Bacteroides (BPB). LDH activity showed a significant positive correlation with levels of B gingivalis and total lactosenegative BPBs. AS levels correlated significantly with B gingivalis only. In these studies no at-

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tempts were m a d e to correlate increases in levels of these enzymes to changes in attachment. AST is an intracellular enzyme that is released and can be detected in crevicular fluid as a result of cell death. Chambers et a156and Persson et aP 7 have shown that AST m e a s u r e m e n t s correlate with gingival inflammation and seem to differentiate sites with spontaneously occurring gingivitis in steady states, from sites with active gingival inflammation. In a longitudinal study, Crawford et a158 showed that elevated levels of AST in gingival crevice samples exhibited a strong correlation with loss of attachment. Prostaglandin E2 is r e p o r t e d to be a principal biochemical mediator of periodontal tissue destruction in humans. T h e r e is a clear association between the levels present within the periodontal tissues and crevicular fluid and the state of periodontal health. 57-61When considering gingivitis, adult periodontitis, and juvenile periodontitis, crevicular fluid levels are low or nondetectable in health, and are elevated markedly with increased disease severity. Extremely high levels of prostaglandin E2 are present at periodontal sites with active loss of attachment. In sites that are in remission or showing no loss, low concentrations are found. It can be concluded that high levels of prostaglandin Ez constitute a significant active disease indicator and that a diagnostic kit assessing concentration could be a valuable tool. A n u m b e r of soluble mediators are p r o d u c e d by inflammatory cells. The identification ofinterleukins and cytokines that could contribute to tissue destruction in periodontal disease has increased interest in cre~icular fluid levels of these mediators. 62,63

Anti-inflammatory Approach to the Treatment of Periodontal Diseases Over the last years, considerable interest has been focused on the use of nonsteroid antiinflammatory drugs to modulate the host response and research has shown that such compounds can retard b o n e loss. Controlled studies have n o t e d this effect in adult and refractory periodontal disease using systemic flurbiprofen therapy and in rapidly progressive periodontal disease using n a p r o x e n or m e c l o t e n a m a t e sodium therapy. 64-68 Because of the c o n c e r n of side effects with the use of systemic therapy 69 of these drugs, the

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concept of local therapy has been approached. 7° In a 6-month controlled study, the effect on b o n e height was evaluated for three different regimens: ketorolac rinse (0.1%) with placebo capsule twice daily (BID); flurbiprofen capsule (50 mg) with placebo rinse BID; or placebo capsule and placebo rinse BID. Significant b o n e loss was observed in the placebo group but not in the flurbiprofen or ketorolac rinse groups. Data indicate that topical application of ketorolac may be beneficial in the t r e a t m e n t of adult periodontal disease.

Smoking Smoking seems to be an i m p o r t a n t risk factor for periodontal diseases and for the refractory f o r m in particular. Magnusson et a171 and McFarlane et a172 r e p o r t e d that in two groups of 21 and 31 refractory patients, 19 and 28, respectively had a history of smoking. Smoking has also b e e n considered a major risk in adult chronic periodontal disease. 7~-7~ Smoking has a negative impact on healing after both nonsurgical and surgical periodontal therapy. 79,s° It has also b e e n suggested that smoking is associated with increased risk of subgingival infection and that smoking may modulate the periodontal flora, sl

Immunization Experiments using vaccination against specific periodontal pathogens have b e e n p e r f o r m e d by several research groups with the main goal of eliminating existing pathogens and preventing subsequent colonization and growth. McArthur et al s2 described the modulation of colonization by black-pigmented bacteria in squirrel monkeys by immunization with P gingivalis. Ebersole et al a3 r e p o r t e d that P gingivalis immunization significantly reduced the e m e r g e n c e of this species during disease progression in ligature-induced disease in Macacafascicularis. However, immunization with P intermedia had minimal effect on the subgingival plaque in this primate. Persson et al s4 r e p o r t e d that antibody titer and m a x i m u m percentage of P gingivalis in M fascicularis were inversely correlated, indicating that a h u m o r a l i m m u n e response may be effective in reducing P gingivalis overgrowth. Although these animal experiments look promising, it is n o t reasonable

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to assume that i m m u n i z a t i o n in humans will be used in the foreseeable future.

References 1. Gibbs CH, Hirschfeld JG, Lee JG, et al. Description and clinical evaluation of a new computerized periodontal probe--the Florida Probe.J Clin Periodonto11988; 15:137144. 2. Magnusson I, Fuller ~%', Heins PJ, et al. Correlation between electronic and visual readings of pocket depth with a newly developed constant force probe. J Clin Periodontol 1988;15:180-184. 3. Goodson JM, Kondon N. Periodontal pocket depth measurements by fiber optic technology. J Clin Dent 1988;1:35-38. 4. Haffajee AD, Socransky SS, Goodson JM. Comparison of different data analysis for detecting changes in attachment level. J Clin Periodontol 1983; 10:298-310. 5. Magnusson I, Clark WB, Marks RG, et al. Attachment level measurements with a constant force electronic probe. J Clin Periodontol 1988;15:185-188. 6. Glavind L, L6e H. Errors in the clinical assessment of periodontal destruction..[ Periodont Res 1967;9:180-184. 7. L6e H, Anerud A, Boysen H, et al. The natural history of periodontal disease in man. J Periodontol 1978;49:607620. 8. Van der Velden U. Probing torce and the relationship of the probe tip to the periodontal tissues. J Clin Periodonto11979;6:106-114. 9. GoodsonJM, Tanner ACR, Haffajee AD, et al. Patterns of progression and regression of advanced destructive periodontal disease.J Clin Periodonto11982;9:472-481. 10. Yang MCK, Marks RG, Magnusson I, et al. Reproducibility of an electronic probe in relative attachment level measurements.J Clin Periodonto11992;19:541-548. 11. Jeffcoat MK, Williams RC, Hohnan BL, et al. Detection of active alveolar bone destruction in human periodontal disease by analysis of radiopharmaceutical uptake after a single injection of 99m-Tc-methylene diphosphonate. J Periodontol Res 1986;21:677-684. 12. Jeffcoat MK, Jeffcoat RL, Captain K, et al. Attachment level probing with automated CEJ detection: Clinical trials.J Dent Res 1989;68:236 (A440). 13. Birek P, McCulloeh CAG, Hardy V. Gingival attachment level measurements with an automated periodontal probe. J Clin Periodontol 1987; 14:472-477. 14. Low SB, Taylor M, Marks RG, et al. Measuring attachment level with an electronic disk probe. J Dent Res 1989;68:359 A. 15. Osborn J, StoltenbergJ, Huso B, et al. Comparison of measurement variability using a standard and constant force probe.J Periodonto11990;61:497-503. 16. Gerlach RW, Meredith MP, CavanaughJn PE Repeatability of controlled pressure periodontal attachment measurements in a multi-center setting. J Dent Res 1995;74: 128A. 17. Watts TLP. Probing site configuration in patients with untreated periodontitis. A study of horizontal position error. J Clin Periodontol 1989;16:529-533. 18. Gr6ndahl H-G, Gr6ndahl K. Subtraction radiography for

the diagnosis of periodontal bone lesions. Oral Surg Oral Med Oral Patho11983;55:208-213. 19. Gr6ndahl K, Gr6ndahl H-G, Webber RL. Influence of variations in projection geometry on detectability of periodontal bone lesions. A comparison between subtraction radiography and conventional radiographic technique. J Clin Periodontol 1984; 11:411-420. 20. Hausmann E, Christersson L, Dunford R, et al. Usefulness of subtraction radiography in the evaluation of periodontal therapy. J Periodontol Special Issue, 1985; Suppl:4-7. 21. Hausmann E, Dnnford R, Wikesj6 U, et al. Progression of untreated periodontitis as assessed by subtraction radiography. J Periodont Res 1986;21:716-721. 22. Deas DE, Newell DH, Komman KS: Densitometric image analysis for detection of periodontitis.J Dent Res 1989;68: 195A. 23. Cogen RB, Heaven B, Jeffcoat M, et al. Periodontal disease activity determined by digital subtraction radiography.J Dent Res 1989;68:195A. 24. Asikainen S, jousimies-Somer H, Kanervo A, et al. Certain bacterial species and morphotypes in localized juvenile periodontitis and in matched controls. J Periodonto11987;58:224-230. 25. Bragd L, Dahl&n G, Wikstr6m M, et al. The capability of Actinobacillus actinomycetemcomitans, Bacteroides gingivalis and Bacteroides intomedius to indicate progressive periodontitis: A retrospective study. J Clin Periodontol 1987; 14:95-99. 26. Christersson LA, Zambon JJ. Suppression of subgingival ActinobaciUus actinomycetemcomitans in localized juvenile periodontitis by systemic tetracycline. J Clin Periodontol 1993;20:395-401. 27. Christersson LA, Albini B, Zambon j[], et al. Tissue localization of AetinobaciUus actinomycetemcomitans in human periodontitis. I. Light, immunofluorescence and electron microscopic studies. J Periodontol 1987;58:529539. 28. Ebersole JL, Taubrnan MA, Smith DJ, et al. Human immune responses to antigens from Actinobacillus actinomycetemcomitans and the correlation with localized juvenile periodontitis. J Clin hnmunol 1983;3:321-331. 29. Listgarten MA, Lai CH, Evian C1, et al. Comparative antibody titers to Actinobaeillus actinomycetemcomitans in juvenile periodontitis, chronic periodontitis and periodontally healthy subjects. J Clin Periodontol 1981;8: 155. 30. Newman MG, Socransky SS. Predominant cultivable microbiota in periodontosis.J Periodont Res 1977;12:120128. 31. DzinkJL, Socransky SS, Haffajee AD, et al. The predominant cultivable microbiota of active and inactive lesions of destructive periodontal diseases. J Clin Periodontol 1988;15:316-323. 32. Gillespie MJ, Smutko JS, Haraszthy GG, et al. Isolation and characterization of the Carnpylobacterrectus cytotoxin. Microb Patho11993;14:203-215. 33. Loesche ~ . The role of spirochetes in periodontal disease. Adv Dent Res 1988;2:275-283. 34. Socransky SS. Microbiology and periodontal disease: Present status and future considerations. J Periodontol 1977;48:497.

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35. van WinkelhoffAJ, van Steenbergen TJM, de GraaffJ, et al. The role of black-pigmented Bacteroides in human oral infections. J Clin Periodontol 1988; 15:145-155. 36. White D, Mayrand D. Association of oral Bacteroides with gingivitis and adult periodontitis. J Periodont Res 1981;16:259-261. 37. Zambon JJ, Grossi S, Dunford R, et al. Epidemiology of subgingival bacterial pathogens in periodontal disease, In: Genco RJ, McGheeJ, editors. Molecular pathogenesis of periodontal disease. Washington, DC: Am Soc Microbiol 1994;3-12. 38. ZambonJJ, Reynolds HS, SlotsJ. Black-pigmented Bacteroides spp. in the human oral cavity. Infect Immun 1981;32:198-203. 39. Magnusson I, Marks RG, Clark WB, et al. Clinical, microbiological and immunological characteristics of subjects with "refractory" periodontal disease. J Clin Periodontol 1991;18:291-299. 40. Loesche ~J. DNA probe and enzyme analysis in periodontal diagnostics. J Periodontol 1992;63:1102-1109. 41. Savitt ED, Strzempko MN, Vaccaro KK, et al. Comparison of cultural methods and DNA probe analyses for the detection of Actinobacillus actinomycetemcomitans, Bacteroides gingivalis, and Bacteroides intermedius in subgingival plaque samples.J Periodontol 1988;59:431-438 42. French CK, Savitt ED, Simon SL, et al. DNA probe detection of periodontal pathogens. Oral Microbiol Immunol 1986;1:58-62. 43. Slots J, Rams TE. Antibiotics in periodontal therapy: Advantages and disadvantages. J Clin Periodontol 1990; 17:479-493. 44. Slots J, van Winkelhoff AJ. Antimicrobial therapy in periodontics.J Calif Dent Assoc 1993;21:51-56. 45. Goodson JM, Cugini MA, Kent RI,, et al. Multicenter evaluation of tetracycline fiber therapy. I. Experimental design, methods and baseline data. J Periodont Res 1991 ;26:361-370. 46. Goodson JM, Cugini MA, Kent RL, et al. Multicenter evaluation of tetracycline fiber therapy. II. Clinical response.J Periodont Res 1991;26:371-379. 47. van Steenberghe D, Bercy P, Kohl J, et al. Subgingival minoycline hydrochloride ointment in moderate to severe chronic adult periodontitis: A randomized, doubleblind, vehicle-controlled, muhicenter study. J Periodontol 1993;64:637-644. 48. AinamoJ, Lie T, Ellingsen BH, et al. Clinical responses to subgingival application of a metronidazole 25% gel compared to the effect of subgingival scaling in adult periodontitis.J Clin Periodontol 1992;19:723-729. 49. Rifkin BR, Vernillo T, Golub LM. Blocking periodontal disease progression by inhibiting tissue-destructive enzymes: A potential therapeutic role for tetracycline and their chemically-modifiedanalogs.J Periodonto11993;64: 819-827. 50. Golub LM, Ciancio S, Ramamurthy NS, et al. Low-dose doxycycline therapy: Effect on gingival and crevicular fluid collagenase activity in humans. J Periodont Res 1990;25:321-330. 51. Villela B, Cogen RB, Bartolucci AA, et al. Collagenolytic activity in crevicular fluid f r o m patients with chronic adult periodontitis, localized juvenile periodontitis and

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gingivitis and from healthy control subjects. J Periodont Res 1987;22:381-389. Birkedal-Hansen H, Pierson M, Heaven M, et al. Bone loss, GCF flow in human periodontitis. J Dent Res 1989;68:334A. Ciancio S, Waite R, Sipos T, et al. Gingival crevicular fluid collagenolytic activity in diagnosing periodontal diseases. J Dent Res 1989;68:334A. Lamster IB, Hartley LJ, Vogel RI. Development of a biochemical profile for gingival crevicular fluid. Methodological considerations and evaluation of collagedegrading and ground substance
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