Introduction

Host modulation is a relatively new term that has been incorporated into our dental jargon, but it has not been well defined. Host can be defined as “the organism from which a parasite obtains its nourishment,” or in the transplantation of tissue, “the individual who receives the graft.” Modulation is defined as “the alteration of function or status of something in response to a stimulus or an altered chemical or physical environment” (Taber’s Medical Dictionary, 2004). In diseases of the periodontium that are initiated by bacteria, the “host” clearly is the individual who harbors these pathogens; however, it was not clear for many years whether it was possible to modulate the host response to these pathogens and other stimuli leading to the breakdown of the attachment apparatus. Host modulation with chemotherapeutic therapy or drugs is the latest adjunctive therapeutic option for the management of periodontal diseases.

The concept of host modulation is fairly new to the field of dentistry but is universally understood by most physicians who routinely apply the principles of host modulation to the management of a number of chronic progressive disorders such as arthritis and osteoporosis. The concept of host modulation was first introduced to dentistry by Williams⁹⁵ and Golub et al³² and then expanded on by many other scholars in the dental profession. In 1990, Williams concluded “there are compelling data from studies in animals and human trials indicating that pharmacologic agents that modulate the host responses believed to be involved in the pathogenesis of periodontal destruction may be efficacious in slowing the progression of periodontitis.”⁹⁵ In 1992, Golub and colleagues discussed “host modulation with tetracyclines and their chemically modified analogues.”³² The future that these authors described has arrived, and to better understand this new era in disease management, we must first look to the theories of the pathogenesis of periodontitis.

Many clinicians previously believed that periodontal disease was an inevitable consequence of aging and was uniformly distributed in the population. They thought that disease severity was directly correlated with plaque levels (i.e., the worse the oral hygiene, the worse the periodontal disease) and that disease progression occurred in a continuous, linear manner throughout life. Now, as a result of better epidemiologic data, there has been a paradigm shift in how clinicians and scientists view the prevalence and progression of this common disease. It has been well established that periodontal disease is not a natural consequence of aging and disease severity is not correlated with plaque levels. Theories about the pathogenesis of periodontitis have evolved from a purely plaque-associated disease to the more recent hypotheses that place considerable emphasis on the host’s response to the bacteria.¹⁰ The first Surgeon General’s report on “Oral Health in America,” published in 2000, recognized the importance of dental health in the overall general health and well-being of a patient.⁸⁷ Recent research findings indicate possible associations between chronic oral infections, such as periodontitis, and systemic disorders, such as diabetes, cardiovascular and lung diseases, stroke, osteoporosis, and rheumatoid arthritis. The Surgeon General’s report assesses these emerging associations and explores factors that may underlie oral-systemic disease connections. Along with these findings and the emergence of the discipline of periodontal medicine, there have been many developments in therapeutic approaches to the management of periodontitis. The development of the chemotherapeutic approach known as “host modulation” required a thorough understanding of the host response and the impact of a variety of risk factors.

Anecdotally, any dentist will be able to identify patients with abundant plaque and calculus deposits with widespread gingivitis and shallow pocketing but with minimal deep pocketing. By contrast, other patients, despite maintaining a high standard of plaque control, succumb to aggressive forms of periodontitis, with deep pocketing, tooth mobility, and early tooth loss. The former group of patients is periodontal disease resistant, whereas the latter group is periodontal disease susceptible. Clearly, the response of the periodontal tissues to plaque is different in these two types of patients, and certain patients undergo advanced periodontal breakdown even though they achieve a high standard of oral hygiene. The previous observations led researchers to realize that the host response to the bacterial challenge presented by subgingival plaque is perhaps the most important determinant of disease severity, progression, and even response to therapy. Although plaque bacteria are capable of causing direct damage to the periodontal tissues (e.g., by release of H₂S, butyric acid, and other enzymes and mediators), it is now recognized that the great majority of the destructive events occurring in the periodontal tissues result from activation of destructive processes that occur as part of the host immune-inflammatory response to plaque bacteria. The host response is essentially protective by intent but paradoxically can also result in significant tissue damage, including breakdown of connective tissue fibers in the periodontal ligament and resorption of alveolar bone.

In 1985, research began to focus on bacterial-host interactions.⁵³ It had been recognized that although bacterial pathogens initiate the periodontal inflammation, the host response to these pathogens is equally, if not more, important in mediating connective tissue breakdown, including bone loss. It has become clear that the host-derived enzymes known as the matrix metalloproteinases (MMPs), as well as changes in osteoclast activity driven by cytokines and prostanoids, cause most of the tissue destruction in the periodontium.⁶³ This shift in paradigms, with a focus on the host response, led to the development of host modulatory therapies to improve therapeutic outcomes, slow the progression of disease, and allow for more predictable management of patients with periodontitis. This therapeutic strategy not only may be relevant to individuals at greater risk for periodontal disease but also may be important in the management of those at risk for a number of related systemic diseases. To better understand the host factors that clinicians are attempting to modulate, we need a more detailed assessment of the role of the host response in periodontal pathogenesis (Figure 48-1). After the accumulation of subgingival plaque bacteria, a variety of microbial substances, including chemotactic factors such as lipopolysaccharide (LPS), microbial peptides, and other bacterial antigens, diffuse across the junctional epithelium into the gingival connective tissues. The periodontium is anatomically unique in that the junctional epithelium ends on the tooth surface, which is nonliving tissue; there is no other such discontinuous lining over the entire surface of the body. The dentogingival junction indicates a priori vulnerability to bacterial attack. Epithelial and connective tissue cells are thus stimulated to produce inflammatory mediators that result in an inflammatory response in the tissues. The gingival vasculature dilates (vasodilation) and becomes increasingly permeable to fluid and cells. Fluid accumulates in the tissues, and defense cells migrate from the circulation toward the source of the chemotactic stimulus (bacteria and their products) in the gingival crevice. Neutrophils, or polymorphonuclear leukocytes (PMNs), predominate in the early stages of gingival inflammation to phagocytose and kill plaque bacteria. Bacterial killing by PMNs involves both intracellular mechanisms (after phagocytosis of bacteria within membrane-bound structures inside the cell) and extracellular mechanisms (by release of PMN enzymes and oxygen radicals outside the cell). As bacterial products enter the circulation, committed lymphocytes return to the site of infection, and B lymphocytes are transformed to plasma cells, which produce antibodies against specific bacterial antigens. Antibodies are released in the gingival tissues and, in the presence of complement, facilitate and enhance PMN phagocytosis and bacterial killing.

Figure 48-1 Schematic illustration of the pathogenesis of periodontitis. The microbial challenge presented by subgingival plaque bacteria results in an upregulated host immune-inflammatory response in the periodontal tissues that is characterized by the excessive production of inflammatory cytokines (e.g., interleukins, tumor necrosis factor), prostanoids (e.g., prostaglandin E₂) and enzymes, including the matrix metalloproteinases (MMPs). These proinflammatory mediators are responsible for the majority of periodontal breakdown that occurs, leading to the clinical signs and symptoms of periodontitis. The process is modified by environmental (e.g., tobacco use) and acquired risk factors (e.g., systemic diseases) and genetic susceptibility. PMNs, Polymorphonuclear leukocytes; LPS, lipopolysaccharide.

(Modified from Kornman KS: Clin Infect Dis 28:520, 1999.)

Thus a host immune-inflammatory response is established in the gingival tissues, and the clinical signs of gingivitis develop. This response is essentially protective in intent, to combat the bacterial infection and prevent ingress of bacteria into the tissues. In persons who are not susceptible to periodontitis (disease resistant), these primary defense mechanisms control the infection, and chronic inflammation (i.e., chronic gingivitis) may persist indefinitely. In disease-susceptible individuals, however, inflammatory events extend apically and laterally to involve deeper connective tissues and alveolar bone. There is proliferation of the junctional epithelium, which becomes increasingly permeable and ulcerated, thus accelerating the ingress of bacterial products, and the inflammation worsens. Further defense cells are recruited to the area, including macrophages and lymphocytes. Large numbers of PMNs migrate into the tissues, secreting excessive quantities of destructive enzymes and inflammatory mediators. These enzymes include the MMPs, such as collagenase and gelatinase, which break down collagen fibers in the gingival and periodontal tissues. The infiltrating inflammatory and immune cells are accommodated by the breakdown of structural components of the periodontium. MMPs are a primary target for host modulation. Pharmacologic agents or chemotherapeutics can be administered to suppress excessive levels of MMPs.

Macrophages are recruited to the area and are activated (by binding to LPS) to produce prostaglandins (e.g., prostaglandin E₂ [PGE₂]), interleukins (e.g., IL-1α, IL-1β, IL-6), tumor necrosis factor alpha (TNF-α), and MMPs. The cytokines (interleukins and TNF-α) and prostanoids are additional targets for host modulatory therapeutics. Interleukins and TNF-α bind to fibroblasts, which are stimulated to produce additional quantities of PGE₂, interleukins, TNF-α, and MMPs in positive-feedback cycles. The concentration of these enzymes and inflammatory mediators becomes pathologically high in the periodontal tissues. Host modulatory therapy (HMT) can be used to interrupt these positive-feedback loops and ultimately reduce the excessive levels of cytokines, prostanoids, and enzymes resulting in tissue destruction. MMPs break down collagen fibers, disrupting the normal anatomy of the gingival tissues and resulting in destruction of the periodontal ligament. The inflammation extends apically, and osteoclasts are stimulated to resorb alveolar bone by the high levels of prostaglandins, interleukins, and TNF-α in the tissues. The osteoclasts themselves are targets for host modulation. Drugs can be administered to downregulate osteoclastic activity and ultimately to inhibit bone resorption by these cells.

The elevations in the proinflammatory or destructive mediators in response to bacterial challenge are counterbalanced by elevations in antiinflammatory or protective mediators such as the cytokines IL-4 and IL-10, as well as other mediators, such as IL-1ra (receptor antagonist), and tissue inhibitors of metalloproteinases (TIMPs) (Figure 48-2). Under conditions of health, the antiinflammatory or protective mediators serve to control tissue destruction. If there are adequate levels of these antiinflammatory or protective mediators to keep the host response to the bacterial challenge in check, the individual will be disease resistant. If an imbalance occurs, with excessive levels of the proinflammatory or destructive mediators present in the host tissues, tissue destruction will ensue in the susceptible host. Another potential target for host modulation could entail the use of pharmacologic agents, which either mimic or result in elevations of endogenous antiinflammatory or protective mediators.

Figure 48-2 The periodontal balance. The balance between periodontal breakdown (“disease”) and periodontal stability (“health”) is tipped toward disease by risk factors, excessive production of inflammatory cytokines and enzymes (e.g., IL-1 and IL-6, interleukin-1 and -6; PGE₂, prostaglandin E₂; TNF-α, tumor necrosis factor alpha; MMPs, matrix metalloproteinases), underactivity or overactivity of aspects of the immune-inflammatory host response, poor compliance, and a pathogenic microflora. The balance can be tipped toward health by risk factor modification, upregulation, and restoration of balance between naturally occurring inhibitors of inflammation (e.g., IL-4 and IL-10, interleukins-4 and -10; IL-1ra, interleukin-1 receptor antagonist; TIMPs, tissue inhibitors of metalloproteinases), HMT (host modulatory therapy), and antibacterial treatments such as OHI (oral hygiene instructions), SRP (scaling and root planing), surgery, antiseptics, and antibiotics.

Thus plaque bacteria initiate the disease, and bacterial antigens that cross the junctional epithelium drive the inflammatory process. Therefore bacteria are essential for periodontitis to occur, but they are insufficient by themselves to cause disease. For periodontitis to develop, a susceptible host is also required. The majority of periodontal breakdown (bone loss, attachment loss) is caused by host-derived destructive enzymes (MMPs) and inflammatory mediators (prostaglandins, interleukins) that are released during the cascade of destructive events that occur as part of the inflammatory response⁶⁶ (see Figure 48-1). Paradoxically, the inflammatory response, which is essentially protective in design, is responsible for much of the breakdown of the soft and hard periodontal tissues. Periodontal disease is characterized by high concentrations of MMPs, cytokines, and prostanoids in the periodontal tissues, whereas periodontal health is characterized by the opposite.⁶⁵ The purpose of HMT is to restore the balance of proinflammatory or destructive mediators and antiinflammatory or protective mediators to that seen in healthy individuals. Pocket formation occurs as coronal junctional epithelium is broken down and restored at a more apical location. Plaque bacteria then migrate apically along the root surface deeper into the pocket, where the physical conditions favor the proliferation of gram-negative anaerobic species. Bacterial products continue to challenge the host, and the host continues its frustrated response against these bacteria and their products. Inflammation extends further and further apically, more bone is resorbed, and periodontal ligament (PDL) is broken down. The pocket deepens, and the associated attachment and bone loss result in clinical and radiographic signs of periodontitis. Intervention is required to prevent eventual tooth loss and other sequelae of the disease.

The nature of the host response to the presence of plaque is modified by genetic factors (helping to explain why aggressive periodontitis tends to have a familial aggregation) and systemic and environmental factors (e.g., smoking, diabetes, stress).

These risk factors may lead to the imbalance between the proinflammatory and antiinflammatory mediators seen in susceptible individuals (see Figure 48-2). Risk factors can affect onset, rate of progression, and severity of periodontal disease, as well as response to therapy^22,38,80 (Box 48-1). Risk assessment is extremely important as we now recognize that some of these risk factors can be modified to reduce a patient’s susceptibility to periodontitis. Risk reduction strategies may include smoking cessation, improved control of diabetes, nutritional supplementation, improved oral hygiene, changes in medication, stress management, weight loss, and more frequent dental visits (Box 48-2). The use of chemotherapeutic agents or drugs specifically designed to treat periodontal diseases is emerging to aid as a risk reduction strategy.

Systemically Administered Agents

Locally Administered Agents

Host Modulation and Comprehensive Periodontal Management

The term periodontal management suggests a much broader concept of periodontal care than the term periodontal treatment. This concept is extremely important considering the chronic nature of the disease. Management includes thorough medical and dental history and examination (clinical charting and radiographs), assessment of risk factors, diagnosis, development of a treatment strategy, initial and definitive treatment planning, review of treatment outcomes and reevaluation, long-term supportive periodontal therapy (maintenance care), and assessment of prognosis. In addition, as new data continue to emerge regarding biochemical assessments of disease activity (measuring levels of proinflammatory mediators, bone and connective tissue breakdown products in the GCF, saliva, and tissues of the oral cavity), new diagnostic and prognostic tests may become part of our established protocols for comprehensive periodontal disease management in the future. However, controlling the bacteria that cause periodontal infections remains a central focus of effective periodontal treatment. Understanding the importance of the host response and the impact of risk factors now allows clinicians to provide complementary treatment strategies simultaneously for their patients (Figure 48-4).

Figure 48-4 Complementary treatment strategies in periodontitis. The best chance for clinical improvement may come from implementing complementary treatment strategies that target different aspects of the periodontal balance. Reduction of the bacterial burden by scaling and root planing (SRP) is the cornerstone of treatment and can be augmented by the use of topical antimicrobials and surgical pocket therapy. In addition to this antibacterial treatment approach, the host response can be treated by the use of host modulatory therapy, such as sub-antimicrobial-dose doxycycline, for the inhibition of matrix metalloproteinases (MMPs). Risk factor assessment and modification must form a key part of any periodontal treatment strategy, including smoking cessation counseling. These different but complementary treatment strategies can be used together as part of a comprehensive management approach.

Those patients most likely requiring the use of HMT include those with risk factors that are either nonmodifiable or not easily modified. If the decision is made to use HMT, this must be discussed with the patient and the rationale for treatment thoroughly explained. This takes time at the chairside, but it is time well spent; patients become increasingly interested in their periodontal status and are more likely to develop ownership of their management, thereby enhancing compliance with all aspects of care, including plaque control, risk reduction, and treatment protocols. Compliance with HMT is greatly facilitated if the rationale for prescribing is clearly explained. The need for compliance with the prescribed drug regimen is important because with SDD, for example, a tablet must be taken twice daily (once in the morning and once in the evening) and should not be taken with calcium supplements. Compliance may be improved by administration of a modified-release SDD capsule taken only once a day. It should be emphasized to the patient that the use of HMT is not a substitute for excellent plaque control (just as it is not a substitute for excellent debridement and root surface instrumentation by the treating clinician). To achieve the best results, patients must be interested and well informed about their condition so that compliance is maximized. Furthermore, patients must also be convinced that comprehensive and frequent recall appointments are absolutely necessary in the maintenance phase of this chronic and often progressive disease, which can be very well controlled with adequate follow-up.

In addition to patient motivation, oral hygiene instruction, and SRP to reduce the bacterial challenge, a key treatment strategy when managing periodontitis patients is risk factor modification. The harmful effects of smoking on the periodontal tissues are well documented,⁴⁶ and successful smoking cessation therapy will likely be a major benefit to patients with periodontitis. Smoking cessation counseling can be undertaken in the dental office (if staff are appropriately trained) or through collaboration with the patient’s physician or specialized clinics. Given the evidence that smokers have worse periodontal disease than nonsmokers^83,99 and that the magnitude and predictability of clinical improvements after treatment are significantly reduced in smokers,^1,69 smoking cessation counseling should form a major part of treatment for smokers with periodontitis. Patients with poorly controlled diabetes are also at increased risk for periodontitis,⁵⁴ and periodontal therapy may have an impact on diabetic control.³⁶ Collaboration with medical colleagues when treating diabetic patients with periodontitis is warranted to ascertain the degree of diabetic control.²¹ Other possible risks for periodontitis include nonmodifiable factors such as genetics, gender, and race. As the relevance of different risk factors is established through epidemiologic research, clinicians must remain aware of their responsibilities for informing and changing patients’ behaviors in relation to modifiable risks.

The management of patients with periodontitis can therefore involve the following complementary treatment strategies:

It is the responsibility of the dentist to customize the treatment plan for each individual patient by selecting and providing appropriate treatments, following discussion and informed decision making by the patient. Good communication and showing an interest in the patient’s condition are essential to maximize compliance and modify risk factors. The best chance for clinical improvement may come from a combination of targeted treatment approaches for each patient (see Figure 48-4). In fact, Novak et al published very striking improvements in probing depth reductions and clinical attachment level gains in a 6-month, randomized, multicenter, examiner-blinded, placebo-controlled study, which showed that combination therapy of HMT (SDD) plus a locally delivered antimicrobial (doxycycline hyclate gel) and SRP provided optimal improvements in clinical parameters when compared to SRP alone in the treatment of moderate-to-severe periodontitis.⁶¹

Sub-Antimicrobial-Dose Doxycycline (SDD)

As previously discussed, SDD is currently the only FDA-approved, systemically administered HMT indicated specifically in the treatment of periodontitis. SDD is used as an adjunct to SRP and must not be used as a stand-alone therapy (monotherapy). Because SDD, previously called “low-dose doxycycline” (LDD) and currently marketed as Periostat, is based on a sub-antimicrobial dosage of doxycycline, a member of the tetracycline family of compounds, the use of tetracyclines for the management of periodontal diseases must be put in perspective.

In regard to incorporation of a medical pharmacologic approach into the management of a disease in the dental practice setting, no class of drugs has made more of an impact on periodontal therapy than the tetracyclines. They have been used in conjunction with SRP, the “gold standard” of nonsurgical therapy, as well as with both resective and regenerative surgical procedures. The tetracyclines have been used locally and systemically as antimicrobial agents and more recently, systemically as a host modulation agent (SDD). The tetracyclines have been prescribed not only to address chronic periodontitis but also to manage specific and often more aggressive types of periodontitis. Most recently, the tetracyclines have been advocated for the management of patients with systemic diseases such as diabetes and rosacea (Oracea); doxycycline has led to improvements in both the periodontal health of compromised diabetic patients and long-term markers of glycemic control (e.g., glycated hemoglobin).³⁷ As an adjunct to mechanical therapies, the goal of tetracycline therapy has been to enhance reattachment or even to stimulate new attachment of the supporting apparatus and osseous formation.

This section concentrates on the use of these pleiotropic compounds for modulation of the host response in the treatment of periodontitis.

Mechanisms of Action

In addition to its antibiotic properties, doxycycline (as well as the other members of the tetracycline family) has the ability to downregulate MMPs, a family of zinc-dependent enzymes that are capable of degrading extracellular matrix molecules, including collagen.^6,78 MMPs are secreted by the major cell types in the periodontal tissues (fibroblasts, keratinocytes, macrophages, PMNs, endothelial cells) and play a key role in periodontitis. Excessive quantities of MMPs are released in inflamed periodontal tissues, resulting in breakdown of the connective tissue matrix. The predominant MMPs in periodontitis, particularly MMP-8 and MMP-9, derive from PMNs³⁰ and are extremely effective in degrading type I collagen, the most abundant collagen type in gingiva and periodontal ligament.⁵² Levels of PMN-type MMPs have been shown to increase with severity of periodontal disease and decrease after therapy.^24,30 The release of large quantities of MMPs in the periodontium leads to significant anatomic disruption and breakdown of the connective tissues, contributing to the clinical signs of periodontitis.

The rationale for using SDD as a HMT in the treatment of periodontitis is that doxycycline downregulates the activity of MMPs by a variety of synergistic mechanisms, including reductions in cytokine levels, and stimulates osteoblastic activity and new bone formation by upregulating collagen production (Figure 48-5).

Figure 48-5 Schematic of periodontal pocket indicating the pleiotropic mechanisms by which doxycycline inhibits connective tissue breakdown. Downregulation of destructive events occurring in the periodontal tissues by doxycycline results from modulation of a variety of different proinflammatory pathways.

(From Golub LM, Lee HM, Ryan ME, et al: Adv Dent Res 12:12, 1998.)

Clinical Research Data On Distinct Patient Populations

Tetracyclines work well as host modulation agents because of their pleiotropic effects on multiple components of the host response (see Figure 48-3). The only enzyme (MMP) inhibitors that have been approved for clinical use and tested for the treatment of periodontitis are members of the tetracycline family of compounds. In early studies investigating the use of different commercially available tetracyclines, Golub et al³¹ reported that the semisynthetic compound (e.g., doxycycline) was more effective than the parent compound tetracycline in reducing excessive collagenase activity in the GCF of chronic periodontitis patients. Because doxycycline was found to be a more effective inhibitor of collagenase than either minocycline or tetracycline^9,25 and because of its safety profile, pharmacokinetic properties, and ready systemic absorption, recent clinical trials have focused on this compound. In an effort to eliminate the side effects of long-term tetracycline therapy, especially the emergence of tetracycline-resistant organisms, SDD capsules were prepared and tested.³⁰ Each capsule contained 20 mg of doxycycline versus the commercially available 50 mg and 100 mg, antimicrobially effective, capsules or tablets. Multiple clinical studies using sub-antimicrobial doses of doxycycline have shown no difference in the composition or resistance level of the oral flora.^85,93 More recent studies also demonstrate no appreciable differences in either fecal or vaginal microflora samples.⁹¹ In addition, these studies have shown no overgrowth of opportunistic pathogens, such as Candida, in the oral cavity, gastrointestinal system, or genitourinary system.

With regard to MMP inhibition, Golub et al²⁴ reported that a 2-week regimen of SDD reduced collagenase in GCF and in the adjacent gingival tissues surgically excised for therapeutic purposes. Subsequent studies using SDD therapy adjunctive to routine scaling and prophylaxis indicated continued reductions in the excessive levels of collagenase in the GCF after 1 month of treatment. After cessation of SDD administration, however, there was a rapid rebound of collagenase activity to placebo levels, suggesting that a 1-month treatment regimen with this host modulation agent was insufficient to produce a long-term benefit.³ In contrast, during the same study, a 3-month regimen produced a prolonged drug effect without a rebound in collagenase levels to baseline during the no-treatment phase of the study. The mean levels of GCF collagenase were significantly reduced (47.3% from baseline levels) in the SDD group versus the placebo group, who received scaling and prophylaxis alone (29.1% reduction from baseline levels). Accompanying these reductions in collagenase levels were gains in the relative attachment levels in the SDD group.^3,29 Continuous drug therapy over several months appears to be necessary for maintaining collagenase levels near normal over prolonged periods. However, it is reasonable to speculate that levels of these MMPs will eventually increase again in the more susceptible patients, and those individuals having the most risk factors and the greatest microbial challenge will require more frequent HMT than other patients.

General Patient Populations

Data from clinical trials of SDD are summarized in Table 48-1. In addition, a series of double-blind, placebo-controlled studies of 3, 6, and 9 months’ duration all showed clinical efficacy based on reductions in probing depth and gains in clinical attachment as well as biochemical efficacy, based on the inhibition of collagenase activity and protection of serum α₁-antitrypsin (a naturally occurring protective mediator) from collagenase attack in the periodontal pocket.^14,25,47 Golub et al²⁷ showed that a 2-month regimen of SDD significantly decreased both the level of bone-type collagen breakdown products (ICTP; carboxy terminal peptide, a pyridinoline-containing cross-linked peptide of type I collagen) and MMP-8 and MMP-13 enzyme levels (neutrophil and bone-type collagenase) in chronic periodontitis subjects (Figure 48-6).

TABLE 48-1 Summary of Data Reported in Clinical Trials of Sub-Antimicrobial-Dose Doxycycline (SDD)⁷²

Figure 48-6 Effect of sub-antimicrobial-dose doxycycline (SDD) on gingival crevicular fluid (GCF) collagenase (MMP-8, MMP-13) and ICTP. A 2-month regimen of SDD significantly decreased levels of matrix metalloproteinases (MMP-8 and MMP-13, neutrophil and bone-type collagenases, respectively) and ICTP compared with placebo in GCF samples of adult periodontitis patients. Decreased levels of GCF bone-type collagen breakdown products (ICTP, pyridinoline-containing cross-linked peptide of type I collagen) in the SDD group versus the placebo group provides biochemical evidence of a reduction in bone resorption. RIA, Radioimmunoassay.

(From Golub LM, Lee HM, Greenwald RA, et al: Inflamm Res 46:310, 1997.)

The Phase III, 9-month, randomized, double-blind, placebo-controlled trial conducted at five dental centers demonstrated clinical efficacy and safety of SDD versus placebo as an adjunct to SRP. The benefits of HMT as an adjunct to mechanical therapy were again seen, with statistically significant reductions in probing depths and gains in clinical attachment levels, as well as the prevention of disease progression.¹² When SDD administration was discontinued after 9 months of continuous therapy, the incremental improvements demonstrated in the SDD group were maintained for at least 3 months. There was no rebound effect in either the pocket depth reductions or the clinical attachment level gains; in fact, there appeared to be slight continued improvement in both these clinical parameters, presumably because of the enhanced clinical status of the patients who had benefited from adjunctive SDD, and possibly also because of the known persistence or substantivity of doxycycline in the bone and soft tissue of the periodontium. The clinical relevance of such findings confirms the utility of an MMP inhibitor in the management of chronic periodontitis.

High-Risk Patients: Smokers

The harmful effects of cigarette smoking and the reduced response to periodontal treatment in smokers compared with nonsmokers are well established.⁴⁶ A recent metaanalysis of randomized clinical trials of SDD used as an adjunct to SRP revealed a benefit when using SDD in smokers with periodontitis^60,70 (see Table 48-1). A hierarchic treatment response was observed such that nonsmokers who received SDD demonstrated the best clinical improvements and smokers who received placebo had the poorest treatment response. The responses of the smokers who received SDD and the nonsmokers who received placebo were intermediate to the two extremes and were broadly identical. This suggests that even patients traditionally considered resistant to periodontal treatment (i.e., smokers) can benefit from SDD, with a treatment response similar to that expected when treating a nonsmoker by scaling and root planing alone.

Special Patient Populations

More recent Phase IV (i.e., post-licensing) clinical studies have revealed success using SDD in particular populations of susceptible individuals. Much interest has focused on genetic susceptibility to periodontal disease, particularly whether a specific variation in the genes that regulate the cytokine IL-1 confers increased susceptibility to disease. This polymorphism is known as the periodontitis-associated genotype (PAG), the presence of which can be characterized using a commercially available screening test, the PST genetic susceptibility test. Investigation of patients who possess this gene polymorphism has been driven by the assumption that local phenotypic differences exist in chronic periodontitis associated with this genotype (e.g., that PAG-positive patients produce more IL-1 cytokines for a given bacterial challenge, resulting in increased tissue damage and more extensive periodontal disease). However, few studies exist of the impact of cytokine gene polymorphism on tissue IL-1 cytokine levels in periodontal disease to support this, although IL-1β levels in shallow periodontal pockets have been reported to be higher in patients with the genotype than those without.¹⁹ The studies that have investigated associations between PAG and periodontal disease status have thus far generated conflicting data (as reviewed by Taylor et al).⁸⁴ A reasonable assumption currently is that there are genetic associations between polymorphisms in the IL-1 gene cluster and periodontal disease but that unambiguous results are not yet apparent because of the heterogeneity of the disease and/or the variable design of the reported studies. Cullinan et al concluded that IL-1 genotype is a contributory but nonessential risk factor for periodontal disease progression.¹⁵

A 5-month preliminary investigation by Ryan et al⁷⁹ was designed to evaluate the impact of treatment on IL-1 and MMP levels in PST-positive patients who presented with elevated levels of these biochemical markers in their GCF. These patients were initially treated with SRP, resulting in no change in the levels of these biochemical markers after 1 month. Al-Shammari et al² reported similar findings, with no changes in GCF levels of IL-1β and ICTP before and after SRP in patients who had not been genotyped. When the genotype-positive patients received SDD and these biochemical markers were monitored at 2 and 4 months, a significant decrease (50% to 61%) in the IL-1β and MMP-9 levels was noted after treatment with SDD. Correspondingly, gains in clinical attachment and reduced probing depths were also observed. The study concluded that a sub-antimicrobial dose of doxycycline may provide PST-positive patients with a therapeutic strategy that specifically addresses their exaggerated host response.

Another recent study was conducted in susceptible patients with severe generalized periodontitis using host modulation (SDD) as an adjunct to repeated subgingival debridement.⁶² Seventy percent of the patients who completed this 9-month double-blind, placebo-controlled study were smokers. SDD as an adjunct to mechanical therapy versus mechanical therapy alone resulted in significantly greater mean probing depth reductions in pockets of 7 mm or greater at baseline as early as 1 month after therapy (2.52 mm versus 1.25 mm, respectively). These improvements in the SDD group compared with the group receiving mechanical therapy only were maintained during the 5.25 months of therapy (2.85 mm versus 1.48 mm, respectively) and even at 3 months after stopping drug therapy (3.02 mm versus 1.41 mm), demonstrating that no rebound effect occurred. Because of the beneficial effects of HMT in susceptible patients, multicenter studies are using SDD in other susceptible populations, including diabetic, osteoporotic, and institutionalized geriatric patients, as well as smokers.

Since periodontitis is associated with many systemic diseases (e.g., osteoporosis, diabetes, and cardiovascular disease [CVD]), researchers have investigated the effect of SDD on these systemic conditions. Payne et al⁶⁷ recently conducted a 2-year randomized, double-blind, placebo-controlled trial in osteopenic women at two dental centers demonstrating that SDD can effectively reduce the levels of localized and systemic inflammatory mediators in osteopenic patients in addition to improving on the clinical measurements of periodontitis²⁸; SDD significantly reduced the progression of periodontal attachment loss⁷⁵ and the severity of gingival inflammation and alveolar bone loss in postmenopausal osteopenic women.⁶⁷ Golub et al²⁸ reported that collagenase activity in the GCF of these osteopenic women was significantly reduced by SDD treatment. ICTP showed a similar pattern of change during SDD treatment with GCF collagenase activity and ICTP levels positively correlated at all time periods (p < 0.001). MMP-8 accounted for approximately 80% of total collagenase in the GCF, with much lower levels of MMP-1 and -13. SDD dramatically reduced the elevated MMP-8 levels by 60%. This 2-year study also demonstrated that long-term continuous use of SDD did not produce antibiotic side effects,⁹² confirming what had been reported previously in studies of continuous use of up to 12 months. Other studies have shown that SDD reduces systemic inflammatory biomarkers in CVD patients⁸ and SDD decreases glycosylated hemoglobin assay (HbA1c) in patients who are taking normally prescribed hypoglycemic agents.¹⁸ The impact of SDD therapy on periodontitis may be amplified by the concurrent use of other HMTS used to manage other inflammatory diseases. Additional studies are being conducted to investigate the impact of combined HMT use not only on periodontal disease but on other chronic inflammatory conditions.

Emerging Host Modulatory Therapies

In the future, a variety of HMTs will likely be developed as adjunctive treatments for periodontitis. One of the most promising groups of potential HMTs is the chemically modified tetracyclines (CMTs). These nonantibiotic tetracycline analogs are tetracycline molecules that have been modified to remove all antibiotic properties, but which retain host modulatory, anticollagenolytic effects. The CMTs are also designed to be more potent inhibitors of proinflammatory mediators and can increase levels of antiinflammatory mediators such as IL-10. Because they have no antimicrobial properties, the clinician would be able to increase the dose for more susceptible patients with more risk factors and who might be more difficult to manage without getting side effects seen with antibiotics. CMTs, such as CMT-3 and CMT-8 (both of which lack antibiotic activity but retain anti-MMP activity), have been shown to inhibit osteoclastic bone resorption and promote bone formation,⁸¹ enhance wound healing,⁶⁸ and inhibit proteinases produced by periodontal pathogens.³⁵ CMTs also are being studied for other effects, such as inhibition of tumor cell invasion⁴⁹ and attenuation of intimal thickening after arterial injury.⁴⁴ CMTs will likely emerge as drugs that have beneficial effects in a variety of disease states because of their host modulation capabilities.

Other potential HMTs include the novel anticytokine drugs developed for the management of rheumatoid arthritis, a disease with a pathobiology similar to that of periodontitis.⁵⁷ Cytokines such as TNF-α have been targeted by TNF-α antagonists (e.g., Infliximab, Etanercept), which have been shown to be effective in treating rheumatoid arthritis.⁹⁰ As yet, such drugs have not been evaluated in the treatment of periodontal disease, but they could offer potential benefits given the importance of inflammatory cytokines, such as TNF-α, in periodontal pathogenesis. In addition, drugs designed to increase the levels of antiinflammatory or protective mediators, such as IL-1ra, can perform similar functions. In addition, evidence is emerging to support the benefits of combining HMTs that target different aspects of the disease processes. For example, the combination of SDD with bisphosphonates has also showed synergy in animal models of bone loss.

Recent research has indicated that there is an active biochemical resolution phase involved in inflammation. Failure of this resolution pathway may play a role in the pathogenesis of periodontal diseases.⁸⁸ Restoration of the resolution pathway by the introduction of resolving molecules may provide new potential therapeutic methods for the management of inflammatory periodontitis.⁷ In rabbit animal models of periodontitis, topical application of Resolvin E1 has been shown to protect bone loss mediated by osteoclasts.⁴⁰ In the future, a combination of antiinflammatory drugs with resolving agents tested in human clinical trials may provide evidence to support a brand new host modulation therapy for the management of periodontal diseases.

Host Modulation Factors in Systemic Disorders

In susceptible patients demonstrating an excessive local inflammatory response to the bacterial stimuli leading to periodontal disease, another consideration involves the loss of epithelial integrity in the periodontal pocket. This tissue response allows for bacterial penetration into the inflamed tissues and eventual entry of the bacteria into the systemic circulation. Patients with untreated periodontitis have an increased risk for transient bacteremias. Bacteremia and associated endotoxemia may incite the overproduction of destructive proinflammatory mediators at distant sites in the periodontitis patient. Therefore patients with periodontitis may be at greater risk for developing a number of systemic conditions associated with a similar overactive host response to external stimuli such as cardiovascular disease and diabetic complications. Elevated levels of cytokines, prostanoids, and enzymes are evident in all these conditions.

In the era of periodontal medicine, systemic host modulatory approaches need to be considered. As mentioned, host modulators used to manage periodontal disease, such as an MMP, cytokine, and prostanoid inhibitors, may have additional beneficial effects on systemic diseases that have been linked to periodontal disease, such as CVD and diabetes. In CVD, preliminary studies have indicated that individuals with periodontal disease are almost twice as likely to have a fatal heart attack and three times as likely to have a stroke.⁴ MMPs and cytokines have been found to play a major role in weakening the plaques formed with CVD, leading to rupture and eventual thrombosis and infarction.²³ In fact, Golub et al²⁶ suggested that tetracyclines could reduce the incidence of acute myocardial infarction⁵⁶ by blocking collagenase and stabilizing the collagen cap on the atheroscleromatous arterial plaques. In diabetes, the same MMPs and cytokines involved in the development of periodontitis as the sixth long-term complication of diabetes⁵⁵ also play a role in the development of other well-known complications of diabetes such as nephropathy, angiopathy, retinopathy, and wound-healing problems.⁷⁷ Modulation of these proinflammatory mediators in diabetic patients may impede the development of multiple long-term complications. An inhibitor of MMPs, cytokines, and prostanoids used in the treatment of periodontitis may have an indirect effect on these disease processes if a patient’s risk for developing these disorders is increased by the presence of untreated periodontitis. HMT may also directly aid in the treatment and prevention of CVD and diabetic complications.

Summary

Periodontal pathogens and destructive host responses are involved in the initiation and progression of periodontitis. Therefore the successful long-term management of this disease may require a treatment strategy that integrates therapies that address both etiologic components. Evidence for the role of MMPs, cytokines, and other mediators in the pathogenesis of periodontal disease distinguishes them as viable targets for a chemotherapeutic approach. The introduction of novel, adjunctive therapies such as host modulation to enhance the efficacy of existing mechanical procedures can contribute favorably to an integrated approach for the long-term, clinical management of periodontitis.

HMTs are an emerging treatment concept in the management of periodontitis. The use of HMT as an adjunct may be particularly useful in susceptible, high-risk patients in whom a prolonged and excessive host response to the presence of bacteria promotes the activity of MMPs and osteoclasts. SDD is the only systemically administered HMT currently approved and indicated as an adjunct to SRP for treating periodontitis. Clinical trials have demonstrated a clear treatment benefit when using SDD versus SRP alone. SDD should be used as part of a comprehensive treatment strategy that includes antibacterial treatments (SRP, plaque control, oral hygiene instruction, local antimicrobials, and periodontal surgery), host response modulation (SDD), and assessment and management of periodontal risk factors. In the future, a range of HMTs targeting different aspects of the destructive cascade of breakdown events in the periodontal tissues are likely to be developed as adjunctive treatments for periodontitis. The further development of these agents will permit dentists to treat specific aspects of the underlying biochemical basis for periodontal disease. The goal is to maximize the treatment response by reducing inflammation and inhibiting destructive processes in the tissues, which will result in enhanced periodontal stability after conventional periodontal treatments such as SRP and surgery. The dentist is now in the exciting position to be able to combine established treatment strategies with new systemic and local drug treatments for this common, chronic disease.

The findings discussed with regard to the use of HMT to better manage chronic periodontal disease may have applications to other chronic systemic diseases such as arthritis, diabetes, osteoporosis, and cardiovascular disease. In addition, studies utilizing locally applied antimicrobials as part of an intensive periodontal therapy (IPT) regimen have shown very promising results. Future studies may demonstrate that in addition to our current standard therapies, IPT with adjunctive antibiotics and/or host modulation for the management of periodontal disease may have profound positive effects on the overall health status of high risk patients. The proper management of local infection and inflammation (periodontitis) will have a significant impact on general overall health of the population.