Introduction
Patients presenting with either significant amount of periodontal tissue loss at a younger age or significant amount of tissue loss over a shorter period may be categorized as Aggressive Periodontitis. The condition may be universally distinguished from chronic periodontitis by the age of onset of disease, rate of disease progression, nature and composition of associated subgingival microflora, alterations in the host immune response and a familial aggregation of diseased individuals.1 The response of aggressive periodontitis to conventional periodontal treatment is unpredictable, and the overall prognosis for these patients is rated to be poorer than for the patients with chronic periodontitis.2 Unfortunately, a single standard protocol has not yet been established focusing definitive therapy to aggressive nature of this disease.
Research on pathogenesis of periodontitis have seen a significant shift from a purely plaque associated hypothesis towards host response to bacteria. The precise nature of the host inflammatory response is still an area of intense research, but it is clear that many host-derived pro-inflammatory mediators play a significant role in the breakdown of periodontal ligament and alveolar bone resorption. A novel approach in the treatment of aggressive periodontitis involves administrating of agents like sub-microbial dose of Doxycycline (SDD) to modulate the host response. The study by Lee et al showed that SDD as an adjunct to mechanical debridement resulted in clinical improvement in patients with generalized aggressive periodontitis (GAP).3 The purpose of the present study is to evaluate the effectiveness of surgical therapy with adjunctive host modulation therapy using Doxycycline Hyclate 20mg in patients with GAP.
Materials and Methods
A total of 60 patients with GAP were enrolled into the study, who were systemically healthy aged between 20 to 40 years with a minimum of 20 teeth in the existing dentition. Individuals with medical conditions like diabetes, hypertension, kidney and liver diseases, pregnant and lactating mothers, females on oral contraceptives and hypersensitivity to tetracyclines. The selected patients were equally divided in to two groups, Group A were placed on SDD 20mg twice a day for 09 months immediately after scaling and root planing followed by periodontal surgery & Group B consisted of matched individuals treated with scaling and root planing followed by periodontal surgery.
Study Medication: Cap Doxycycline Hyclate 20 mg (SDD)
Doxycycline Hyclate 20 mg (SDD) is the only FDA approved host modulatory agent till-date. The commercial brands of this semisynthetic tetracycline compound are Periostat (Collagenex pharmaceuticals) and Atridox (Teva pharmaceuticals). These preparations are commercially not available in India. Capsules of Doxycycline Hyclate 20mg were therefore dispensed from capsules of Doxycycline Hyclate 100mg under sterile conditions in collaboration with a pharmaceutical laboratory.
Prescription of study medication and assessment of compliance: At baseline the patients in group A received a 30days supply of these SDD capsules. They were instructed to take one capsule each in morning and evening with at approximately 12 hours interval between the two either 1 hour before or 2 hours after meals. The patients were instructed that antacids and nutritional supplements containing Al, Ca or Mg might impair drug absorption and that these were to be taken 1.5 hours before or 3 hours after taking the study medication. The patient compliance and adverse effects if any were monitored during monthly visits throughout the medication period, during which they received additional supply of SDD capsules for the subsequent 30 days.
The eligibility of patients enrolled into the study was determined based on the inclusion/exclusion criteria followed by complete clinical and radiological examination of each subject. The probing depth (PD) and the clinical attachment levels (CAL) were measured at 06 sites per tooth with a William’s periodontal probe and an orthopantomograph (OPG) was taken for assessment of bone loss. In addition to these, Oral Hygiene Index -Simplified (OHI-S), Bleeding on Probing (BOP), and Gingival Index (GI) were recorded. Then the patients were randomly distributed into group A and group B.
The patients in both group A and B were subjected to full mouth scaling and root planing with strict oral hygiene instructions. The study medications(SDD) were given to patients in group A immediately after SRP. Thereon, the patients in both the groups were kept under observation for a period of four weeks prior to surgical phase. The patients demonstrating PD and CAL ≥5mm and ≤10mm with atleast five teeth in a quadrant four weeks after phase I therapy were taken up for periodontal surgery. A full mouth periodontal surgery was performed quadrant wise at a biweekly interval. These patients were evaluated at 90, 180 and 270 days post-operatively. All subjects were assessed for the clinical parameters (probing depth, clinical attachment level, oral hygiene index-simplified & gingival index at baseline and post operatively at 90 days, 180 days and 270 days.
Results
The group A subjects presented with a mean probing depth of 4.9104 (±0.69342) at baseline while the group B subjects presented with a 4.8184 (±0.42414). The inter-group comparison of PD values revealed a statistically highly significant difference between group A and group B at 90 days, 180 days and 270 days post-operatively with ‘p’ value = 0.000 (Table 1 & Figure 1). The group A subjects presented with a mean CAL of 5.6948 (±0.76865) at baseline while the group B subjects presented with a 5.0392 (±0.61635). Group A & group B are comparable on CAL values at baseline as there is no statistically significant difference between mean CAL of both groups by unpaired t test with a ‘p’ value = 0.07. The inter-group comparison of probing CAL revealed a statistically significant difference between group A and group B at post-operative 90 days and 180 days with ‘p’ value = 0.043 and 0.039 respectively, but no statistically significant difference between group A and group B at post-operative 270 days with ‘p’ value = 0.067(Table 2 & Figure 2).
The inter-group comparison regarding percentage bleeding scores, revealed that the scores at baseline as well as post-operative 90,180 and 270 days were statistically insignificant with ‘p’ value > 0.05(Table 3 & Figure 3). There is a statistically significant change in GI scores compared between baseline and follow up period time points, but no statistically significant difference post operative 90 days onwards in both the groups (Table 4 & Figure 4). The inter-group comparison regarding OHI-S scores, revealed that the scores at baseline as well as 90,180 and 270 days post- operatively were statistically insignificant with ‘p’ value > 0.05(Table 5 & Figure 5).
Table 1
Intergroup comparison of mean probing depth
Table 2
Intergroup comparison of clinical attachment levels
Table 3
Intergroup comparison of bleeding on probing
Table 4
Intergroup comparison of gingival index score
Table 5
Intergroup comparison of OHI-S scores
Discussion
Periodontal treatment through the ages has focused on reduction of bioburden through mechanical means. However, recent research into the pathogenesis of periodontal diseases has led to a paradigm shift in understanding that host response is a crucial stage in periodontal disease progression and that major component of tissue destruction is due to activation of host immune-inflammatory defense mechanisms in response to the bacterial plaque.4
Host modulatory therapy (HMT) is a widely accepted, novel therapeutic approach in the management of periodontitis, particularly as an adjunct to mechanical therapies, non-surgical and surgical.5 The clinical trials by Golub et al tested specially formulated capsules containing lower-than-usual amounts of minocycline or doxycycline regimens with 20% of the recommended daily dose of antibiotic and reported substantial reduction of the GCF collagenase activity during a 2-week course of treatment leading to the proposition that, in-vivo SDD administration reduces pathologically excessive collagenase activity in gingiva and GCF and hence could be used to control and suppress the progression of periodontal disease.6
Doxycycline Hyclate 20mg, is currently the only FDA approved, systemically administered HMT indicated specifically in the treatment of periodontitis.7 Most of clinical research data available to-date have focused on use of SDD as an adjunct to nonsurgical periodontal treatment.8, 9, 10, 11, 12 These randomized controlled clinical trials reported improvements in clinical outcomes without detrimental shifts in the normal periodontal flora or the acquisition of doxycycline resistance and no rebound/delayed or negative after effects for a 03 month period after cessation of therapy, suggesting safety and efficacy of adjunctive SDD therapy.13, 14
However, very limited data is available regarding the efficacy of SDD used as an adjunct to surgical therapy. Gapski et al in 2004 & 2009 conducted randomized controlled trials using SDD as adjunct to access flap surgery in patients with chronic periodontitis reporting efficacy with consistent results.15, 16 There are no studies on similar lines to assess the efficacy of SDD as adjunct to surgical therapy in patients with aggressive periodontitis. Hence, the present study was taken up. The current study is also distinct with respect to duration of SDD therapy being 09 months aligning with Caton et al., who have reported prolonged sustainance of clinical benefits with 09 months administration of adjunctive SDD. 8 Golub et al., have suggested that an extended period of SDD therapy is necessary for maintaining the collagenase levels near normal over prolonged periods translating clinically as improvement in clinical attachment levels.17 The microbiological parameters have not been evaluated in the current study as some studies have demonstrated no significant difference in cultivable anaerobic flora and recovery of periodontal pathogens in treatment groups following SDD therapy.8
The purpose of the present study was to evaluate the effectiveness of surgical therapy with adjunctive Doxycycline Hyclate 20mg bid for 09 months in patients with GAP and investigate additive effects of SDD on the clinical parameters like PD, CAL, BOP, GI and OHI-S.
The subjects were randomly distributed in each group ruling out any selection bias. There was no statistically significant difference in demographic parameters, age and sex between the study groups. At baseline only the patients in group A received a 30 days supply of SDD capsules. The patient compliance and any accompanying adverse effects were monitored at monthly visits throughout the medication period. The surgical procedure indicated for subjects enrolled into the study was conventional undisplaced sulcular incision flap surgery as they exhibited moderate to severe bone loss.
The reduction in PD observed were significantly greater for group A at every post-baseline time point than for group B. Improvements from baseline were 22% greater in group A than with group B, consistent with those of Gapski et al. 15, 16 The potential mechanisms that explain the results may be that SDD promotes rapid wound maturation by inhibiting collagen disruption and indirectly encouraging collagen formation.
Improvements in the attachment levels were observed from baseline at all post-baseline time points in both group A & B in this study. However, improvements in the attachment levels were statistically significantly greater with group A than group B at 90 and 180 days post-operatively, again consistent with that by Gapski et al, except no statistically significant difference in the attachment levels between groups A and B at post-operative 270 days.15, 16 The above is also concurrent with those of a meta analysis of 2011.17, 18
The results of current study revealed a significant reduction in percentage of sites exhibiting BOP in both group A and group B. But, the inter-group comparison regarding percentage bleeding scores, it was noticed that the scores at baseline as well as post-operative 90,180 and 270 days were statistically insignificant, concurrent with Golub et al who suggested that the improvements in periodontal condition by SDD therapy was mainly by inhibiting collagen destructive enzymes rather than affecting microbially-induced inflammation.10
In the present study, improvements in the GI and OHI-S scores were observed from baseline for both the groups at all post-baseline time points. However, they were statistically insignificant with intergroup comparison of these parameters from baseline to post-operative 90,180 and 270 days. This was consistent with that of Golub et al who suggested that, the improvements in GI was due to oral prophylaxis received at the baseline and probable improvements in self-performed oral hygiene.10
The adverse effects were correspondingly distributed between group A and B. 07 patients (04 from group A and 03 from group B) reported with adverse events during the course of the study. Overall oral adverse events included post-surgical pain and tooth sensitivity. No serious adverse events or discontinuations owing to adverse events were observed in the current study. No adverse event was considered to be probably related to SDD, showing that SDD was tolerated well.
The adjunctive use of SDD improves the clinical responses above and beyond those attainable by mechanical therapy alone. In order to maximize the potential for benefit when using adjunctive SDD, mechanical therapy must be undertaken with highest standards. This is the responsibility of the treating clinician who must also explain the rationale for prescribing adjunctive SDD to the patient. It takes time to explain the role of SDD to the patient, but this is important to ensure compliance.
Conclusion
The periodontal destruction involves a complex interplay between pathogens and the host tissues resulting in loss of attachment and formation of periodontal pockets. The need to restore the natural balance between tissue destructive enzymes and their inhibitors has led to a novel management strategy that focused on modulation of host response. SDD has been a time tested formulation directed to down-regulate destructive phase.
The present study conducted to evaluate and compare the efficacy of sub-antimicrobial dose doxycycline (SDD) in patients with generalized aggressive periodontitis. Analyzing the observations, it could be concluded that, adjunctive treatment with SDD 20mg twice daily was shown to augment the clinical attachment gains achieved by periodontal surgery and represents a new approach in the long term management of periodontal disease. The small sample size and short follow up period are the major limitations of the present study. Further prospective randomized control studies with larger sample size, longer follow up period, different populations and additional biochemical parameters are needed to determine the efficacy of SDD as an adjunct to periodontal surgeries. Moreover, disease progression rates in individual tooth sites vary over the course of the clinical trial and disease progression rates may influence the magnitude of clinical improvements.
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