Aggressive periodontitis

aggressive periodontitis, aetiopathogenesis, clinical features,

1. AGGRESSIVE PERIODONTITIS PRESENTED BY: PRABLEEN ARORA MDS STUDENT

2. Periodontitis is an infection that can have many different clinical presentations. Aggressive Periodontitis ( AgP ) comprises of a group of rare, often severe, rapidly progressive forms of periodontitis often charaterized by an early age of clinical manifestation and a distinctive tendency for cases to aggregate in families.

3. HISTORICAL BACKGROUND 1923, Gottlieb reported a patient with fatal case of epidemic influenza and a disease he called “ diffuse atrophy of alveolar bone ”. Characterized by Loss of collagen fibres in PDL and their replacement by loose connective tissue & extensive bone resorption ; leading to widened PDL space. 1928: Gottlieb attributed it to inhibition of continuous cementum formation (considered essential for maintenance of PDL fibres ). He termed it “ deep cementopathia ”; this was a disease of eruption.

4. 1938: Wannenmacher described incisor-first molar presentation and called it “ parodontitis marginalis progressive ”. Many authors ( Goldman 1947 , Gottlieb 1923 ) considered this to be degenerative, non inflammatory disease process and gave it the name “ periodontosis ”. 1966: World Workshop in Periodontics concuded that the concept of “ periodontosis ” as a degenerative entity was unsubstantiated and the term should be eliminated from periodontal nomenclature. “ Juvenile Periodontitis ”: given by Chaput & colleagues in 1967 and Butler in 1969. 1971: Baer defined it as a ‘disease of the periodontium occuring in an otherwise healthy adolescent which is characterized by a rapid loss of alveolar bone about more than one tooth of permanent dentition.

5. 1989: World Workshop in Clinical Periodontics categorized the disease as Localised Juvenile Periodontitis(LJP), a subset of broad classification of early-onset periodontitis (EOP) . Under this classification system, age of onset and distribution of lesions were of primary importance when making a diagnosis of LJP . More recently, disease with the characteristics of LJP has been renamed as LOCALIZED AGGRESSIVE PERIODONTITIS (LAP). In the 1999 Classification Workshop of the American Academy of Periodontology , a consensus report adopted the term aggressive periodontitis as a new name for this unique disease classification , replacing the term early-onset periodontitis .

6. CLASSIFICATION AND CLINICAL SYNDROMES Aggressive forms of periodontal disease have been defined based on the following primary features . Lang et al (1999): Non contributory medical history Rapid attachment loss and bone destruction. Familial aggregation of cases.

7. SECONDARY FEATURES Amounts of microbial deposits inconsistent with the severity of periodontal tissue destruction. Elevated proportions of Aggregatibacter actinomycetamcomitans and in some Far East populations, Porphyromonas gingivalis . Phagocyte abnormalities . Hyper-responsive macrophage phenotype, including elevated proportions of PGE2, IL-1b. Progression of attachment loss and bone loss may be self arresting.

8. Subclassification of AgP (International classification Workshop) By Lang et al (1999) ; Tonetti & Mombelli (1999 ) Localised aggressive periodontitis (LAP) Circumpubertal onset Localised first molar/incisor presentation with interproximal attachment loss on atleast two permanent teeth, one of which is a first molar, and involving no more than two teeth other than first molars and incisors . Robust serum antibody response to infecting agents.

9. CLINICAL & RADIOGRAPHIC PICTURE OF LAP

10. A striking feature is lack of clinical inflammation despite the presence of deep periodontal pockets and advanced bone loss. Plaque on the affected teeth is minimal. The plaque that is present forms a thin biofilm on the teeth and rarely mineralizes to form calculus .

11. Other clinical features: Distolabial migration of maxillary incisors with diastema formation. Increasing mobility of maxillary and mandibular incisors and first molars. Sensitivity to denuded root surfaces to thermal and tactile stimuli. Deep dull radiating pain during mastication probably caused by irritation of the supporting structures by mobile teeth and impacted food.

12. Radiographically Vertical loss of alveolar bone around the first molars and incisors beginning around puberty- classic diagnostic sign of LAP Arc shaped loss of alveolar bone extending from distal surface of second premolar to mesial surface of second molar.

13. The following possible reasons for the limitation of periodontal destructon to certain teeth have been suggested: After initial colonization of first permanent teeth to erupt, A.a evades the host defences by different mechanisms including production of PMN chemotaxis -inhibiting factors , endotoxins , collagenases , leukotoxins and other factors that allow the bacteria to colonize the pocket and initiate destruction of periodontal tissues. After this initial attack, adequate immune defenses are stimulated to produce opsonic antibodies. to enhance the clearence and phagocytosis of invading bacteria and neutralise leukotoxic activity. In this manner, colonization of other sites may be prevented.

14. Bacteria antagonistic to Aggregatibacter actinomycetamcomitans colonize the periodontal tissues and inhibit Aggregatibacter actinomycetamcomitans from further colonization therefore localizing A.a infection and tissue destruction. 3. Aggregatibacter actinomycetamcomitans may lose its leukotoxin -producing ability ; progression becomes arrested or impaired and colonization of new sites may be averted. 4. A defect in cementum formation may be responsible for localization of lesions.

15. GENERALIZED AGGRESSIVE PERIODONTITIS (GAP) Usually affecting persons < 30 yrs; may be older. Generalized interproximal attachment loss affecting atleast three permanent teeth other than first molars and incisors. Pronounced episodic nature of destruction of attachment and alveolar bone. Poor serum antibody response to infecting agent.

16. Two types of gingival responses seen: 1.Severe,acutely inflamed tissues, often proliferating, ulcerated and fiery red. ( DESTRUCTIVE STAGE ) Bleeding may be spontaneous or with slight stimulation. Suppuration may be an important feature. 2. Tissues may appear pink, free of inflammation, and occasionally with some degree of stippling. Page and Schroeder believed that this type of response coincides with periods of quiescence in which bone levels remain stationary. Systemic manifestations can be seen like fever, weight loss, mental depression, and general malaise.

17. Radiographically Can range from severe bone loss associated with minimum number of teeth to advanced bone loss affecting the majority of teeth in the dentition.

18. EPIDEMIOLOGY All available investigations, however , indicate that early onset (aggressive) forms of periodontal diseases are detectable in all age and ethnic groups ( Papapanou 1996) . 51.5 % affected individuals. These differences are probably due to differences in the employed epidemiological methodologies and definition of EOP.

19. PRIMARY DENTITION Little evidence is available concerning the prevalence of Aggressive periodontitis affecting the primary dentition . In the few studies from industrialized countries, marginal alveolar bone loss has been found to affect the primary dentition of 5 to 11 year olds with frequencies ranging from 0.9-4.5% of subjects (Sweeney et al. 1987 ) . More severe cases affecting the primary dentition and leadind to tooth exfoliation early in life are usually interpreted as periodontal manifestation of systemic diseases- leukocyte adhesion deficiency.

20. PERMANENT DENTITION 13 to 20 year old individuals, the majority of studies have reported a prevalence of periodontitis of less than 1 % . Among US school children 5-17 years of age, the prevalence of periodontitis has been estimated to range from about 0.2% for whites to about 2.6% for blacks ( Loe & Brown 1991 ). Blacks were at much higher risk for LAP, and black males were at 2.9 times higher risk. White females were more likely to have LAP than white males . In a study of untreated periodontal disease conducted by Loe et al. (1986) in Srilanka , 8% of population had rapid progression of periodontal disease, characterized by yearly attachment loss of 0.1-1 mm.

21. SCREENING Cost effective detection of cases require utilization of a sensitive screening approach. Most sensitive diagnostic test is measurement of attachment loss by probing . In younger subjects , currently utilized method is the measurement of the distance between alveolar crest and CEJ on bitewing radiographs. Recent investigations have attempted to determine the ‘Normal’ distance between CEJ and alveolar crest of primary and permanent molars in 7-9 year old children ( Sjodin & Mattson et al 1997).

22. Median distances at primary molars were 0.8-1.4 mm . CEJ of permanent molars was 0-0.5 mm apical to alveolar crest in 7-9 year olds. Most of children present distances significantly smaller than 2-3 mm considered normal for completely erupted dentitions of adults. A distance of 2 mm between CEJ and alveolar crest , in absence of local factors (caries, restorations, open contacts), can be suspected for diagnosis of periodontitis ( Sjoidin & Mattson 1992). In older individuals, PERIODONTAL PROBING is a more appropriate screening method.

23. CIRCUMFERENTIAL PROBING to be done at all the sites around the teeth. The American Academy of Periodontology has recently endorsed a simplified screening examination for this purpose. This examination is based on a modification of Community Periodontal Index of Treatment Needs (CPITN) ( Ainamo et al 1982; AAP & ADA 1992)

24. ETIOLOGY AND PATHOGENESIS Dominant microorganisms in LAP : Aggregatibacter actinomycetamcomitans , Capnocytophaga sp., Eikenella corrodens , Prevotella sp., Campylobacter rectus . Gram positive isolates : streptococci, peptostreptococci . Aggregatibacter actinomycetamcomitans , Capnocytophaga , Prevotella sp. Are predominant members of subgingival flora.

25. Aggregatibacter actinomycetamcomitans Key microorganism in LAP. Short, facultatively anaerobic, non-motile, gram negative rod. This view was principally based on four lines of evidence ( Socransky & Haffajee 1992) : 1. Aggregatibacter actinomycetamcomitans was isolated in more than 90% of LAP patients . In some studies, it was possible to demonstrate elevated levels of A.a in sites showing evidence of recent or ongoing periodontal tissue destruction ( Haffajee et al 1984; Mandell 1984; Mandell et al 1987.)

26. 2. Demonstration of virulence factors : Aggregatibacter actinomycetamcomitans produces several potentially pathogenic substances, including leukotoxin and is capable of inducing disease in experimental animals and non-oral sites. It can translocate across epithelial membranes. ( Zambon et al 1988, Slots & Schonfeld 1991). 3. Findings of immune response towards this bacterium: elevated levels of serum antibodies to Aggregatibacter actinomycetamcomitans in LAP patients ( Listgarten et al 1981, Tsai et al 1981 , Altman et al 1982, Ebersole et al 1982).

27. 4.Clinical studies showing correlation between treatment outcomes and levels of Aggregatibacter actinomycetamcomitans after therapy: unsuccessful treatment outcomes linked to failure in reduction of subgingival load. Consequently, highly sensitive tests detect the bacterium would be useful diagnostic tools. Several studies, provide evidence of transmission between humans; DiRienzo et al 1990; Preus et al 1992; Petit et al 1993; Poulsen et al 1994.

28. Using monoclonal antibody technology, five serotypes ( a,b,c,d,e ) of Aggregatibacter actinomycetamcomitans can be distinguished . Serotype b strains often isolated from patients with localized juvenile periodontitis than from other subjects ( Zambon et al 1983, 1996). Several properties of Aggregatibacter actinomycetamcomitans are regarded as important determinants of virulence and pathogenic potential . L eukotoxin production is considered highly significant since it may play important role in A.a’s evasion of local host defences .

29. LEUKOTOXIN : role in evasion of local host defences . Belongs to family of RTX (Repeats in ToXin ), which are pore-forming lytic toxins . Exhibits cytotoxic specificity and destroys human PMN leukocytes and macrophages , but neither epithelial and endothelial cells, nor fibroblasts. Serotype-b strain (JP2 Clone) present in high frequency in patients with LJP. This strain was isolated from African American child with prepubertal periodontitis (Tsai et al 1984).

30. FACTOR SIGNIFICANCE LEUKOTOXIN Destroys human PMN leukocytes and macrophages. ENDOTOXIN Activates host cells to secrete inflammatory mediators (PGs, IL-1b, TNF-a BACTERIOCIN May inhibit growth of beneficial species IMMUNOSUPPRESSIVE FACTORS May inhibit IgG and IgM production. COLLAGENASES CHEMOTACTIC INHIBITION FACTORS Cause degradation of collagen. May inhibit neutrophil chemotaxis

31. Gram negative bacteria consists of lipopolysaccharide (LPS). A.a can secrete membrane vesicles that can serve as transport vehicles to spread endotoxin as well as other pathogenic substances produced by bacterium. LPS can activate host cells & macrophages to secrete inflammatory mediators such as Prostaglandins, IL-1b, TNF-a. It is highly immunogenic, since high titers of antibodies against its antigenic determinants are frequently detected in infected individuals

32. Dominant organisms in GAP Porphyromonas gingivalis , Bacteroides forsythus and A.a . A.a is facultative anaerobe; P.gingivalis and B. forsythus are fastidious strict anaerobes. P. gingivalis produce collagenases , proteases, endotoxins , fatty acids, other possibly toxic agents (Shah 1993). High local and systemic immune responses against this bacterium have been demonstrated in patients with GAP.

33. BACTERIAL DAMAGE TO PERIODONTIUM Two related mechanisms: 1. Direct action of the microorganism or their products on the host tissues. 2. Results of the eliciting tissue damaging inflammatory responses. Investigations have indicated that A.a is able to translocate through junctional epithelium and invade the underlying connective tissue ( Saglie et al 1988).

34. Apical spread of bacteria loosely adhering to hard, non shedding surface of tooth is thought to be controlled through first line of defence . Mechanisms : High turnover rate of junctional epithelium keratinocytes . Outward flow of GCF. Directed migration of PMN leukocytes through junctional epithelium.

35. HOST RESPONSE TO BACTERIAL PATHOGENS Local inflammatory response characterized by intense recruitment of PMNs both within the tissues and into periodontal pocket. Depressed T-helper cell to T-suppressor cell ratio compared to both healthy gingiva and peripheral blood. High levels of PGE2, IL-1a, IL-1b in both crevicular fluid and peripheral blood. Prostaglandin E2 production is highly elevated in AgP subjects when compared to periodontally healthy individuals and chronic periodontitis patients.

36. IMMUNOLOGICAL FACTORS The human leukocyte antigens (HLAs), which regulate immune responses, have been evaluated as candidate markers for aggressive periodontitis. HLA A9, B15 antigens are consistently associated with aggressive periodontitis. Patients with aggressive periodontitis display functional defects of polymorphonuclear leukocytes (PMNs), monocytes , or both. These defects can impair either the chemotactic attraction of PMNs to the site of infection or their ability to phagocytose and kill microorganisms. Current studies demonstrate hyper responsiveness of monocytes from LAP patients involving the production of PGE2 in response to Lipopolysaccharide . This lead to increased connective tissue or bone loss due to excessive catabolic factors.

37. Possible immune mechanisms include Increase in expression of MHC II, HLA DR4. Polyclonal activation of B cells by microbial plaque. Genetic predisposition.

38. GENETIC ASPECTS OF HOST SUSCEPTIBILITY SEGREGATION ANALYSIS : autosomal dominant inheritance. Segregation analysis provides information about the mode of inheritance of a genetic trait but not about the specific gene involved. LINKAGE ANALYSIS : linkage of LAP to Vitamin D binding locus on region q of chromosome 4 in large family of Brandywine population ( Boughman et al 1986 ). Li et al 2004 : has shown linkage of LAP with q25 region of chromosome 1. Scapoli et al 2005 : showed linkage with q13-14 region of chromosome 2 that contains IL-1 gene complex.

39. Tonetti and Mombelli,1999 summarized that “it seems that specific genes may be different in various populations and/or ethnic groups and therefore true heterogeneity in disease susceptibility may be present. The role of specific genes remains to be elucidated”.

40. ENVIRONMENTAL ASPECTS OF HOST SUSCEPTIBILITY Cigarette smoking was shown to be a risk factor for patients with GAP. ( Schenkein et al 1995). Smokers with GAP have more affected teeth and greater means of attachment loss than patients with GAP who did not smoke. The results indicated that IgG 2 levels as well as antibody levels are significantly depressed in subjects with GAP who smoke . Since these antibodies are considered to represent a protective response against A.a , it is possible that the depression of IgG 2 in smokers may be associated with the observed increase in disease extent and severity.

41. CLINICAL DIAGNOSIS A tentative clinical diagnosis is based on following criteria: Absence of significant systemic conditions . Rapid attachment loss and bone destruction . Familial aggregation of cases. Lack of consistency between clinically visible bacterial deposits and severity of periodontal breakdown.

42. LAP GAP Circumpubertal onset (13-14 to 25 yr old). Localized first molar-incisor presentatio with interproximal attachment loss on atleast two permanent teeth, one of which is first molar and involving no more than two teeth other than first molar. Less than 30-35 years. Generalized interproximal attachment loss affecting atleast three permanent teeth other than first molars and incisors. Pronounced episodic nature of destruction of attachment and alveolar bone.

43. RADIOGRAPHIC DIAGNOSIS Localised Aggressive Periodontitis Generalised Aggressive Periodontitis

44. MICROBIOLOGIC DIAGNOSIS Knowledge of whether a clinical condition is associated with A.a and/or P. gingivalis , has an impact on the need to supplement conventional therapy with antibiotics and choice of antimicrobial drug. Microbiological testing may be postponed until the first phase is completed. Reduction in bacterial load might increase the possibility of false negative results when an insensitive microbiological test is used. Since A.a and P. gingivalis can be transmitted from patients to family members, microbial testing of spouses, children or siblings of AgP patients may be indicated to intercept early disease in susceptible patients .

45. EVALUATION OF HOST DEFENSES Associated with high incidence of phagocyte functional disturbances, such as depressed neutrophil chemotaxis and other phagocyte antibacterial dysfunctions. AgP patients present higher levels of PGE2 in crevicular fluid. The findings indicated that these patients respond to bacterial and inflammatory stimuli with very high levels of local release of inflammatory mediators.

46. GAP patients have decreased ability to mount high titres of specific IgG2 antibodies to A.a . These patients exhibit a tendency towards progressive periodontal destruction leading to tooth loss. LAP have better prognosis and donot express this trait. Serum antibody titres and avidity of A.a may be useful in differential diagnosis of GAP and LAP.

47. GENETIC DIAGNOSIS Clinical determination of different disease forms in family should be followed by construction of a pedigree of the AgP trait. Such diagnosis may bring considerable information regarding the level of risk eventually shared within the family. It helps to establish the need for monitoring clinically unaffected individuals.

48. PRINCIPLES OF THERAPEUTIC INTERVENTION Treatment should be initiated after completion of careful diagnosis. Successful treatment is considered to be dependent on early diagnosis, directing therapy towards elimination or suppression of infecting organisms and providing an environment conducive to long-term maintenance.

49. The prognosis depends on Whether the disease is generalized or localized. Degree of destruction present at the time of diagnosis. Ability to control future progression. GAP rarely undergoes spontaneous remission, whereas LAP have been known to arrest spontaneously. This has been referred to as “BURNOUT” OF THE DISEASE.

50. CONVENTIONAL PERIODONTAL THERAPY Consists of patient education, oral hygiene improvement, scaling and root planing and regular recall maintenance. Teeth with moderate to advanced attachment loss and bone loss often have a poor prognosis . Treatment options for teeth with deep periodontal pockets and bone loss may be non-surgical or surgical . Surgery may be purely resective , regenerative or a combination.

51. RESECTIVE SURGICAL THERAPY Reduces or eliminates pocket depth. If a significant height discrepancy exists between periodontal support of affected teeth and unaffected teeth, the gingival transition will often result in deep probing pocket depth around affected tooth. It is important to realize the limitations of surgical therapy and to appreciate the possible risk that surgical therapy may further compromise teeth that are mobile because of extensive loss of periodontal support. For example, in a patient with severe horizontal bone loss, surgical resective therapy may result in increased tooth mobility that is difficult to manage, and a nonsurgical approach may be indicated. Therefore careful evaluation of the risks versus the benefits of surgery must be considered on a case by- case basis.

52. REGENERATIVE PERIODONTAL THERAPY Use of barrier materials, bone grafts, and wound healing agents. Intrabony defects, particularly vertical defects with multiple osseous walls are often amenable to regeneration with these techniques. Recent advances in regenerative therapy have advocated the use of enamel matrix derivative ( Emdogain ) to aid in regeneration of cementum and new attachment in periodontal defects.

53. ANTIMICROBIAL THERAPY SYSTEMIC ADMINISTRATION Adjunctive antibiotic treatment frequently results in a more favorable clinical response than mechanical therapy alone. In a systematic review, Herrera et al found that systemic antimicrobials in conjunction with scaling and root planing offer benefits over scaling and planing alone in terms of clinical attachment level, probing pocket depth, and reduced risk of additional attachment loss. Genco et al treated localized aggressive periodontitis patients with scaling and root planing plus systemic administration of tetracycline (250 mg four times daily for 14 days every 8 weeks). 18 months after the initiation of therapy. Bone loss had stopped, and one-third of the defects demonstrated an increase in bone level, whereas in the control group, bone loss continued.

54. Liljenberg and Lindhe treated also treated LAP with administration of tetracycline (250 mg 4 times daily for 2 weeks), modified widman flaps, and periodic recall visits every month for 6 months. The lesions healed rapidly and more completely. After 5 years they found that the treatment group continued to demonstrate 1.resolution of gingival inflammation, 2. gain of clinical attachment, 3. refill of bone in angular defects. Systemic antibiotics should only be administered as an adjunct to mechanical debridement because IN UNDISTURBED SUBGINGIVAL PLAQUE, THE TARGET ORGANISMS ARE EFFECTIVELY PROTECTED FROM ANTIBIOTIC AGENT DUE TO BIOFILM EFFECT.

55. Systemic tetracycline ( 250mg of tetracycline hydrochloride four times daily for atleast 1 week ) should be given in conjunction to local mechanical debridement. Doxycycline 100mg/day may be used instead of tetracycline. Chlorhexidine rinses should be prescribed and continued for several weeks to enhance plaque control and facilitate healing.

56. Antibiotics have been essentially used in two ways for treatment: In combination with intensive instrumentation over a short period of time after achievement of adequate plaque control in pretreatment motivation period. As a staged approach after completion of initial therapy.

57. MICROFLORA ANTIBIOTIC OF CHOICE Gram positive Amoxicillin- clavulanate potassium Gram negative Clindamycin Non oral gram negative, facultative rods, Pseudomonas, Staphylococci Ciprofloxacin Black pigmented bacteria & spirochaetes Metronidazole Prevotella intermedia , P.gingivalis Tetracycline A. actinomycetamcomitans Metronidazole -amoxicillin Metronidazole -ciprofloxacin Tetracycline P.gingivalis Azithromycin

58. A randomised controlled clinical trial has provided evidence of a significant benefit arising from treatment approach (Guerrero et al. 2005) : Achievement of adequate supragingival plaque control (less than 25% sites with detectable plaque). Subgingival instrumentation for 2-day period. An adjunctive systemic antibiotic regime consisting of metronidazole (500 mg tid for 7 days) combined with amoxicillin (500 mg, tid for 7 days)

59. LOCAL DELIVERY FORMULATED IN FORM OF SOLUTIONS, GELS, CHIPS, FIBRES . Advantages : Smaller dosages can be administered inside the pocket. No side effects of systemic therapy. Increased exposure of the target microorganism to high concentration therefore more therapeutic levels of medication .

60. FULL MOUTH DISINFECTION Described by Quirynen et al. Full mouth debridement completed in two appointments within a 24 hr period. In addition to scaling and root planing , the tongue is brushed with a chlorhexidine gel (1%) for 1 minute, the mouth is rinsed with a chlorhexidine solution (0.2%) for 2 minutes, and pockets are irrigated with 1% chlorhexidine solution.

61. HOST MODULATION Administration of agents that modulate the host response. Subantimicrobial dose doxycycline (SDD) : help to prevent the destruction of PDL attachment by controlling the activation of MMP’s , primarily collagenase and gelatinase , from both infiltrating cells and resident cells of periodontium , primarily neutrophils . SDD as an adjunct to repeated mechanical debridement resulted in clinical improvement in patients with generalized aggressive periodontitis. Other agents such as flubriprofen , indomethacin , and maproxen may reduce inflammatory mediator production.

62. CONCLUSION Aggressive periodontitis comprises a group of rare, often severe, rapidly progressive forms of periodontitis , characterised by an early age of onset and tendency for cases to aggregate in the families. Diagnosis of one of these forms requires the absence of systemic diseases that may severely impair host defences and lead to premature exfoliation of teeth. Optimal plaque control by patient is of paramount importance for a favourable clinical and microbiological response to therapy.

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