Host Modulation
Host Modulation: Conceptualization to Clinical Trials and Integration into Clinical Practice
Maria Emanuel Ryan, DDS, PhD
Copyright 2002 Journal of the California Dental Association.
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A better understanding of the pathogenesis of periodontitis has resulted in pharmacotherapeutic advancements, addressing both the microbes and the host response, leading to improved management of this chronic progressive disease by the dental practitioner. The adjunctive use of host-modulatory agents can enhance therapeutic responses, slow the progression of the disease, and allow for more-predictable management of patients. This article will review the pathogenesis and risk factors associated with periodontitis and address in detail the concept and clinical utility of host modulation as a therapeutic strategy.
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Introduction
This is truly an exciting time in the field of dentistry because the benefits of the many scientific and technological advances that have occurred during the past 20 years are now entering clinical practice. This is particularly true for the management of periodontitis, the most common dental disorder. These advancements have occurred as researchers better elucidate the causative factors of periodontitis, leading to improved management of this chronic progressive disease. The understanding of the pathogenesis of periodontitis has evolved from purely a plaque-associated disease to the current thinking, which places a renewed emphasis on the host’s response to the bacteria.
The first-ever Surgeon General’s Report on Oral Health in America1 has helped to educate not only the general public but also the medical profession on the potential consequences of the periodontitis. In particular, this report recognizes the importance of dental health in the overall general health and well-being of patients. Along with these findings and the emergence of the discipline of periodontal medicine, there have been developments in adjunctive chemotherapeutic approaches to the management of periodontitis. This article will address the concept and clinical utility of host modulation for the management of periodontal disease. The concept of host modulation is fairly new to the field of dentistry but is a universal concept understood by most physicians and routinely applied in the management of chronic progressive disorders such as arthritis and osteoporosis.
Pathogenesis
Periodontal disease does not appear to behave like a classical infection, but more like an opportunistic infection. There is no way to eliminate bacteria from the oral cavity, so bacteria are always present in the periodontal milieu. When certain more-virulent species exist in an environment that allows for them to be present in greater proportion, there is the opportunity for periodontal destruction to occur. However, while it is apparent that plaque is essential for the development of the disease, the severity and pattern of the disease are not explained solely by the amount of plaque present. In 1985, research began to focus very closely on bacterial-host interactions, leading to the "Host-Bacteria Inter-Relationship Era".2 During this era, it was recognized that although there is evidence that specific bacterial pathogens initiate the pathogenesis of periodontal disease, 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 it is the host-derived enzymes known as the matrix metalloproteinases (MMPs), and changes in osteoclast activity driven by cytokines and other inflammatory mediators known as prostanoids that cause the majority of the tissue destruction in the periodontium3 (Figure 1). This shift in paradigms to a concentration on the host response has led to the development of host-modulatory therapies to improve therapeutic outcomes, slow the progression of disease, allow for more predictable management of patients, and possibly even work as preventive agents against the development of periodontitis.
Risk
There are a number of environmental and acquired risk factors that increase a patient’s susceptibility to periodontitis. The risk factors that can affect onset, rate of progression, and severity of periodontal disease, as well as response to therapy, include:
* Heredity;
* Smoking;
* Hormonal variations such as those seen in pregnancy (where there are increased levels of estradiol and progesterone, which may change the environment and permit the virulent organisms to become more destructive);
* Menopause (in which the reductions in estrogen levels leads to osteoporosis);
* Systemic diseases such as diabetes;
* Immunocompromise, such as with HIV;
* Stress
* Nutrition;
* Medications such as calcium channel blockers;
* Faulty dentistry; and
* A previous history of periodontal disease.4-6
Some of these risk factors can be modified to reduce a patient’s susceptibility. Risk management may include smoking cessation, improved control of diabetes, nutritional supplementation, and stress management. The field of "perioceutics", or the use of pharmacological agents specifically developed to better manage periodontitis, is emerging to aid in the management of these susceptible patients who develop periodontal disease. Host modulatory therapy, which can be used to bring down excessive levels of enzymes, cytokines, and prostanoids as well as modulate osteoclast function is the key to addressing many of these risk factors that have adverse effects on the host response.
Host Modulators
A number of host modulatory agents have been investigated in clinical trials for their potential use as adjuncts to mechanical nonsurgical periodontal therapy. These have included the systemic (Flurbiprofen) and topical (Ketoprofen) use of nonsteroidal anti-inflammatory drugs, the systemic use of sub-antimicrobial dose doxycycline (Periostat) and the systemic use of bisphosphonates (Fosomax). The only systemic host modulatory agent approved by the FDA (Food and Drug Administration) for adjunctive use in conjunction with nonsurgical periodontal procedures is Periostat. The points of intervention of these agents in the host response can be seen in Figure 2. In addition, a number of local host modulatory agents have been investigated in clinical trials for their potential use as adjuncts to surgical procedures not only to improve upon wound healing but also to stimulate regeneration of lost bone, periodontal ligament, and cementum, restoring the complete periodontal attachment apparatus. These have included enamel matrix proteins (Emdogain), bone morphogenetic proteins (BMP-2 and BMP-7), growth factors (platelet-derived growth factor and insulin-like growth factor), and tetracyclines. The only host modulatory agent currently approved by the FDA for adjunctive use during surgery is Emdogain. The paper will focus on the clinical utility of host modulation for nonsurgical procedures in clinical practice, so it will be limited from here on to the use of sub-antimicrobial dose doxycycline (SDD or Periostat) in clinical practice.
Since Periostat is based upon a sub-antimicrobial dosage of doxycycline, a member of the tetracycline family of compounds, it is important to place the use of tetracyclines for the management of periodontal diseases into perspective. As far as incorporation of a medical pharmacological approach to 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 scaling and root planing, the gold standard of nonsurgical therapy, as well as with surgical procedures, both resective and regenerative. The tetracyclines have been used locally and systemically as antimicrobial agents and more recently systemically as a host-modulatory agent. The tetracyclines have been used not only to address chronic adult periodontitis but also for the management of specific, often more aggressive, types of periodontitis. Most recently, the tetracyclines have been advocated for the management of patients with systemic diseases, such as diabetes. The use of tetracyclines has lead not only to improvements in the periodontal health of compromised diabetic patients, but also to improvements in long-term markers of glycemic control such as glycated hemoglobin.7 Clinically, the purpose of using tetracyclines as adjunctive agents has been to kill the pathogens in the tissues and pockets, modulate the host response, and thereby increase the predictability of a variety of periodontal therapies including scaling and root planing. As an adjunct to mechanical therapies, the goal has been to enhance reattachment or even to stimulate new attachment of the supporting apparatus and osseous formation. The literature is replete with references to the use of tetracyclines in the management of periodontal disease, so this paper will concentrate on the use of these pleiotropic or multi-use compounds for modulation of the host response in the treatment of periodontitis.
Clinical Trials on SDD
Tetracyclines work so well as host modulatory agents because of their pleiotropic effects on multiple components of the host response (Figure 2). The only enzyme (MMP) inhibitors that have been tested for the treatment of periodontitis are members of the tetracycline family of compounds. In an early study using these different tetracyclines, Golub and colleagues8 reported that the semisynthetic compounds were more effective than tetracycline HCl in reducing excessive collagenase activity in the gingival crevicular fluid (GCF) of adult periodontitis patients. Because doxycycline was found to be a more effective inhibitor of collagenase than either minocycline or tetracycline,9,10 recent clinical trials have focused on this compound. In an effort to eliminate the side effects of long-term tetracyclines therapy, especially the emergence of tetracycline-resistant organisms, sub-antimicrobial-dose doxycycline (SDD) capsules were prepared and tested.11 Each capsule contained 20 mg of doxycycline, compared to the commercially available 50 and 100 mg, antimicrobially effective, capsules. In multiple clinical studies conducted using sub-antimicrobial dose doxycycline, there has not been a difference in the composition or resistance level of the oral flora,12,13 and more recent studies demonstrate no appreciable differences in either fecal or vaginal microflora samples.13 In addition, these studies have also demonstrated no overgrowth of opportunistic pathogens such as Candida in the oral cavity or gastrointestinal or genitourinary systems.
Early studies indicated that SDD reduced the peak blood level of the drug by 92 percent compared with the regular dose doxycycline regimen based on a bio-assay.14,15 Subsequent studies using high performance liquid chromatography (HPLC) analysis of total doxycycline in the serum indicate that blood levels (Cmax) range from 0.5 to 0.7 mg/ml rather than 0.29 mg/ml previously reported by bioassay. The discrepancy in these findings may be due to the fact that much of the doxycycline measured by HPLC in the serum is bound to serum proteins and would not be available and active when measured by bioassay techniques.
With regards to MMP inhibition, Golub and colleagues16 reported that a two-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 that after one month of treatment there were continued reductions in the excessive levels of collagenase in the GCF, but that after cessation of SDD administration there was a rapid rebound of collagenase activity to placebo levels, suggesting that a one-month treatment regimen with this host modulatory agent was insufficient to produce a long-term benefit.17 In contrast, during the same study, a three-month regimen produced a prolonged drug effect without rebounding to baseline levels during the no-treatment phase of the study. The mean levels of GCF collagenase were significantly reduced (47.3 percent from baseline levels) in the SDD treated group vs. the placebo group, which received scaling and prophylaxis alone (29.1 percent from baseline levels). Accompanying these reductions in collagenase levels were gains in the relative attachment levels in the SDD treated group,17,18 as seen in Figure 3. Continuous drug therapy over a period of several months appears to be necessary for maintaining collagenase levels near normal over prolonged periods. However, it is reasonable to speculate that these MMPs will eventually reappear in the more susceptible patients, and those individuals having the most risk factors and the greatest microbial challenge will require more frequent host modulatory therapy than other patients.
A series of double-blind, placebo-controlled studies of three, six and nine months’ duration, all showed clinical efficacy based on the reduction of pocket depth and inhibition of gingival attachment loss as well as biochemical efficacy, based on the inhibition of collagenase activity, and protection of serum a1-antitrypsin (a naturally occurring protective mediator) from collagenase attack, in the periodontal pocket.9,19,20 Golub and colleagues21 showed that a two-month regimen of SDD significantly decreased both the level of bone-type collagen breakdown products (ICTP; a pyridinoline-containing crosslinked peptide of Type I collagen) and MMP-13 enzyme levels (bone-type collagenase) in adult periodontitis subjects providing biochemical evidence of reduction of bone resorption to support computer-assisted subtraction radiography data,22,23 the latter providing evidence of a reduction in the loss of alveolar bone height after 12 months of therapy with SDD.
There is clear evidence that modulation of the host response -- whether it be by effects on MMPs, cytokines, prostanoids, or osteoclast function -- can play a role in slowing periodontal disease progression. In the case of enzyme suppression, SDD has been found to be useful for preventing disease progression as can be seen in Figure 4, which shows the percentage of tooth sites that lost 3 mm or more of attachment during the 12 month course of a Phase III clinical trial.22,24 Adjunctive treatment with SDD in conjunction with dental scaling and prophylaxis was shown to reduce disease progression by 85 percent, 73 percent and 36 percent in sites with severe, mild-to-moderate, and essentially no disease, respectively. This demonstrates that host modulatory therapy can aid in the maintenance of normal sites, preventing them from developing disease, as well as in the prevention of further progression of disease in already diseased sites. Only with the systemic administration of a drug would it be possible to see effects on the normal sites that are usually ignored due to inadequate diagnostics that would otherwise alert the practitioner to incipient disease activity at these "normal" sites.
Upon analysis for attachment loss of 3 mm or more during the first six months of this 12-month study, a subset of susceptible patients in each treatment arm became evident. As seen in Table 1, there are far fewer sites in the group treated with the host modulatory agent SDD (14 sites) that experienced this rapid loss of attachment compared with the placebo group (52 sites), which corresponds to a 73 percent reduction in the incidence of rapid progression of periodontitis. In addition, when recovery therapy was performed (in this case scaling and root planing with anesthesia) the average attachment gain was significantly greater in the adjunctive SDD group (2.16 mm) than in the adjunctive placebo group (0.78 mm) as measured six months later, 12 months following baseline.17 The adjunctive use of an MMP inhibitor clearly made these most susceptible patients, with active disease sites, more responsive to the more definitive therapy (scaling and root planing), thereby demonstrating almost a reversal in these rapidly progressive sites in the SDD treated group of patients. It is likely that patients who are susceptible to rapidly progressive periodontitis have dysfunctional host responses that would benefit from host modulatory therapy. The same may be true of tooth sites that are refractory to traditional therapies.
A nine-month randomized, double-blind, placebo-controlled trial, conducted at five dental centers demonstrated clinical efficacy and safety of SDD vs. placebo adjunctive to scaling and root planing. Once again, the benefits of host modulatory therapy in addition to mechanical therapy were seen with statistically significant reductions in probing depths, bleeding on probing, and gains in clinical attachment levels as well as the prevention of disease progression.24,25 A clear effect of SDD therapy can be seen with regard to the need for recovery therapy and tooth extraction as seen in Table 2. There are reductions in the numbers of individuals and tooth sites requiring recovery therapy due to rapid attachment loss of 2 mm or more along with less need for extraction in the SDD treated group. In a discontinuation study, where SDD administration was discontinued after nine months of continuous therapy, the incremental improvements demonstrated in the SDD group were maintained for at least three months post-treatment. There was no rebound effect in either the pocket depth reductions or clinical attachment level gains; in fact there appeared to be slight continued improvements in both of these clinical parameters.24,25 The clinical relevance of such findings confirm the utility of an MMP inhibitor in the management of adult periodontitis.
More recent Phase IV clinical studies have revealed success using LDD in very susceptible individuals. One such patient population is one with a specific variation in the genes that regulate the cytokine interleukin-1 (IL-1). Currently there is a PST Genetic Susceptibility Test for Periodontal Disease to determine whether a patient has this susceptible genotype. PST-positive patients have an increased inflammatory response in the presence of bacteria, producing two to four times more IL-1 with microbial challenge.26 Therefore, these patients are at greater risk for developing severe periodontal disease27 and subsequently at greater risk for tooth loss.28 A five-month preliminary investigation by Ryan and colleagues29 was designed to evaluate the impact of treatment on IL-1 and MMP levels of 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 one month. Al-Shammari and colleagues30 reported similar findings with no changes in GCF levels of IL-1b and ICTP before and after scaling and root planing in patients who had not had not been genotyped. When the genotypically positive patients were placed on SDD and these biochemical markers where monitored at two and four months, a significant decrease (50 percent to 61 percent) in the IL-1b and MMP-9 levels was noted after treatment with Periostat. Correspondingly, gains in clinical attachment and reduced probing depths were also observed. The conclusions of the study were that a sub-antimicrobial dose of doxycycline may provide PST-positive patients with a therapeutic strategy that specifically addresses their exaggerated host response. It may be speculated that the subjects of the Al-Shammari and colleagues study may have also benefited from the use of a host modulatory agent. Another recent study was conducted in susceptible patients with severe generalized periodontitis using host modulation as an adjunct to a mechanical therapy known as "repeat sub-gingival debridement."31 Fifty percent of the patients who participated in this nine-month double-blind, placebo-controlled study were smokers. Sub-antimicrobial dose doxycycline as an adjunct to mechanical therapy vs. mechanical therapy alone, respectively, resulted in significant improvements in probing depth reductions, in pockets greater than or equal to 7 mm at baseline, as early as 1 month after therapy (2.52 mm vs. 1.25 mm) which were maintained during the 5.25 months of therapy (2.85 mm vs. 1.48 mm) and even after three months of drug therapy cessation (3.02 mm vs. 1.41 mm), demonstrating that there was no rebound effect. Due to all of these beneficial effects of host modulatory therapy in susceptible patients, multicenter studies are anticipated using SDD in diabetic and osteoporotic patients as well as in institutionalized patients.
Clinical Application
Host modulation with a sub-antimicrobial dose of doxycycline has been FDA approved for adjunctive use with scaling and root planing and has recently been granted the ADA Seal of Approval. The duration of use may vary from patient to patient. A risk factor assessment in addition to clinical evaluation of patients can help to guide the practitioner with regard to length of use and need for repeat use. A minimum of three months of host modulatory therapy is suggested. Patients who are allergic to tetracyclines, pregnant, nursing, or younger than 8 should not take this medication.
The author has implemented a two-pronged approach to periodontal therapy into her clinical practice. The initial visit by a patient will include a medical and dental history, a risk assessment profile (Table 3), periodontal charting, and radiographic analysis. The patient must be made aware of the fact that periodontal disease is not curable but that it can be well-controlled with constant monitoring by the dentist/hygienist and good patient compliance. The patient must also be informed of the need for periodontal therapy, which is not an option but rather a necessity for good general health, as studies have indicated. Initial therapy consists of oral hygiene instructions, which must be continuously reinforced over the course of therapy; scaling and root planing with anesthesia as needed (both approaches designed to reduce the bacterial load); and host modulation to reduce excessive levels of enzymes, cytokines and prostanoids. Modification of any risk factors such as smoking, nutrition, stress, contributing medications, faulty restorations, poor oral hygiene, and poor diabetic control can also be addressed at this time. A patient’s refusal or an inability to modify contributing risk factors are important considerations for treatment planning and evaluation of therapeutic responses. In the case of host modulation, the more risk factors and the poorer the hygiene, the greater the need for host modulation of longer duration or repeat therapy in the future.
After completion of initial therapy, re-evaluation is most critical. At this point, the decision is made to either continue with active (additional) therapy or to place the patient into the maintenance phase. If all probing depths are less than 5 mm, then the decision is made to place the patient into the maintenance phase of therapy. The author will typically keep the patient on the host modulatory agent through the first maintenance visit. If the treated sites remain stable for this three-month period, the patient will be removed from host modulatory agent and placed into the typical maintenance program until additional active therapy is required. If there are probing depths greater than 5 mm at re-evaluation, then the therapeutic approach may differ depending on the number of sites and radiographic assessment of those sites. Typically for isolated sites, a nonsurgical approach may include rescaling the site and placement of a locally applied antimicrobial with the continued adjunctive use of the host modulatory agent. If this is insufficient to achieve adequate pocket depth reduction or if there are multiple sites in a quadrant, then a surgical approach is used to reduce the probing depths through resective or regenerative techniques. Once all probing depths are less than 5 mm, the patient is placed into the maintenance phase of therapy as described above.
In patients truly refractory to the therapy provided above, systemic antimicrobials or additional host modulatory agents have been used, often in a polypharmacologic approach. Examples of additional host modulatory approaches used include low doses of NSAIDS (flurbiprofen), or the newer Cox-2 inhibitors (Vioxx), or low doses of bisphosphonates. These types of patients who are most susceptible with multiple risk factors or patients presenting with moderate-severe disease requiring comprehensive periodontal treatment planning should be referred to the specialist for care and close monitoring.
With regards to periodontal therapy, better diagnostics would be very useful. Therapeutic technologies have surpassed dentists’ ability to adequately diagnose active vs. inactive lesions, to pick up subtle changes in the tissues thereby preventing additional loss of attachment and bone. Studies have shown that scaling and root planing alone may not be sufficient to reduce excessive levels of many of the destructive mediators, particularly in the more susceptible patients. Until such diagnostic techniques are made available, clinicians have no choice but to rely on clinical judgement to determine the most appropriate course of therapy.
Conclusion
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. It is clear that standard therapy, such as the removal of supra- and subgingival plaque and calculus deposits by scaling and root planing results in more predictable outcomes for mild-moderate periodontitis than for moderate-severe periodontitis. The use of a host modulatory agent, or a combination of host modulatory agents, capable of inhibiting MMPs, cytokines, and other mediators of the disease, can assist in the conventional treatment for periodontitis. When used adjunctively, chemotherapeutics can enhance and make clinical therapeutic responses more predictable in the more susceptible patient.
Author
Maria Emanuel Ryan, DDS, PhD, is an associate professor in the Department of Oral Biology and Pathology at the School of Dental Medicine at Stony Brook, N.Y. She is actively involved in teaching, practice, and research at the school. Her research is funded by the National Institutes of Health and industrial sources. She holds U.S. patents for the prevention of long-term complications of diabetes.
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To request a printed copy of this article, please contact/Maria Emanuel Ryan, DDS, PhD, Department of Oral Biology and Pathology, School of Dental Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794-8702, or at Maria.Ryan@stonybrook.edu.
Figure 1. Simplified schematic depicting etiologic factors and cascade of events contributing to periodontitis.
Figure 2. Potential adjunctive therapies and points of intervention in the treatment of periodontitis.
Figure 3. Effect of SDD on GCF collagenase activity and rALv.
Figure 4. Tooth sites losing >3 mm CAL Periostat phase III scaling trial.
