|Year : 2015 | Volume
| Issue : 1 | Page : 15-22
Perioceutics - Where do we stand?
Pavithra Rangarajan Seshadri, Krishnan Viswanathan
Division of Periodontia, RMDCH, Annamalai University, Chidambaram, Tamil Nadu, India
|Date of Web Publication||26-Aug-2015|
Dr. Pavithra Rangarajan Seshadri
No. 8/33, Palandi Amman Koil Street (Near St. Thomas Mount Railway Station), Adambakkam, Chennai - 600 088, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Periodontitis is a multifactorial infectious disease of the supporting structures of the teeth, characterized by destruction of the bone and connective tissue. Specific periodontopathic bacteria and their virulence factors are the primary etiologic agents. However, the interaction of host defense mechanisms and these etiological agents play an important role in the onset and progression of the disease. Research began to focus very closely on bacterial-host interaction, leading to host bacterial interrelationship era. The shift in concentration on host response has led to the development of host modulatory therapies which could 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. This paper reviews the host modulatory therapy, which is the effective means when used as an adjunct to mechanical periodontal therapy in treating periodontal diseases.
Keywords: Host modulation; perioceutics; periodontal disease; periodontal therapy; therapeutic agents
|How to cite this article:|
Seshadri PR, Viswanathan K. Perioceutics - Where do we stand?. Indian J Multidiscip Dent 2015;5:15-22
| Introduction|| |
The term perioceutic (periodontal + therapeutic) was first introduced by Heska Corporation. This field of "Perioceutics," that includes antimicrobial therapy and host modulatory therapy, to produce beneficial changes in the microflora and host response, respectively, has emerged as a vital aid in the management of susceptible patients who develop periodontal disease along with mechanical debridement.  Host can be defined as "The organism from which a parasite obtains 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." 
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 a number of chronic disorders such as arthritis and osteoporosis. This concept to dentistry was introduced by Williams and Golub. Williams in 1990 concluded that, "There are compelling data from animal and human trials indicating that pharmacologic agents that modulate the host responses believed to be involved in the pathogenesis of periodontal destruction may be effective in slowing progression of periodontal disease." 
Host modulation therapy (HMT) is a treatment concept that aims:
- To reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or down-regulating destructive aspects of the host response and up-regulating protective or regenerative responses
- To restore the balance between pro-inflammatory mediators and destructive enzymes on one hand, and on the other hand between anti-inflammatory mediators and enzyme inhibitors. They can be systemically administered or locally delivered and used as adjuncts to scaling and root planning (SRP)  [Figure 1].
|Figure 1: Points of intervention for nonsurgical therapy. CAL: Clinical attachment loss; IL: Interleukin; NSAIDs: Nonsteroidal anti-inflammatory drugs; TNF: tumor necrosis factor|
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| Mechanism of Host Induced Periodontal Destruction|| |
Plaque bacteria including Porphyromonas gingivalis, Prevotella intermedia, Aggregatibactar actinomycetemcomitans, Tannerela forsythia, and perhaps others such as Campylobacter rectus, Fusobacterium nucleatum, and Spirochetes are associated with severe forms of periodontal disease. Their introduction as an exogenous infection and predominance in the pathogenic flora trigger a cascade of immune responses in the host. Once these bacteria colonize, the tooth surface near the gingival margins, bacteria, and their metabolic products and the lipopolysaccharide (LPS) initiate the host response [Figure 2]. The bacteria and their by-products directly challenge the cells of junctional epithelium. In response, the junctional epithelial cells release various inflammatory mediators including cytokines, prostaglandin E2 (PGE2), matrix metalloproteinase (MMPs), and tumor necrosis factor-α (TNF-α). These mediators stimulate the immune response, recruiting neutrophils to the site of periodontal infection. If these inflammatory cells are able to contain bacterial challenge and their products (such as LPS endotoxins) by intercellular killing mechanisms, the disease limits itself to the gingiva. If the bacterial challenge is not controlled by these mechanisms and if pathogens and their products penetrate host tissues, the inflammation worsens and progress to periodontitis. However, if these mechanisms fail and if pathogens and their products penetrate host tissues, the disease becomes periodontitis.
The microbial challenge consisting of antigens, LPS, and other virulence factors stimulates host responses which result in disease limited to the gingiva (i.e., gingivitis) or initiation of periodontitis. Protective aspects of the host response include recruitment of neutrophils, production of protective antibodies, and possibly the release of anti-inflammatory cytokines including transforming growth factor-β, interleukin-4 (IL-4), IL-10, and IL-12. Perpetuation of the host response due to a persistent bacterial challenge disrupts homeostatic mechanisms and results in release of mediators including pro-inflammatory cytokines (e.g. IL-1, IL-6, TNF-α), proteases (e.g. MMPs), and prostanoids (e.g. PGE2), which can promote extracellular matrix destruction in the gingiva and stimulate bone resorption. 
The production of collagenase from infiltrating neutrophils and resident periodontal tissue cells is a part of the natural host response to infection in periodontal disease and other chronic inflammatory diseases. There is an imbalance between the level of activated tissue destroying MMPs and their endogenous inhibitors. These cascades of events from inflammation collectively lead to gingival recession, pocket formation, tooth mobility, and tooth loss. It is clear that host factors play a major role in the pathogenesis of periodontal disease. 
Host modulatory agents can be classified as:
I. Agents preventing progressive disease (destruction)
- Destruction of extracellular matrix - MMP inhibitors (e.g.: Subantimicrobial dose doxycycline [SDD]), chemically modified tetracycline [CMT])
- Destruction of bone - Nonsteroidal anti-inflammatory drugs (NSAID's), bisphosphonates, inhibition of receptor activator of nuclear factor-kappa B (RANK)/receptor activator of nuclear factor-kappa B ligand (RANKL) interaction, hormone replacement therapy, cathepsin K, statins, WnT pathway, Vitamin D, protease activator receptor 2 agonists and antagonists, histone deacetylase inhibitors
- Destruction of extracellular matrix and bone - anticytokine therapy, no inhibition, antagonists to cell adhesion molecules, disruption of cell-signaling pathways, Toll-like receptors modulation, and periodontal vaccines
II. Agents promoting resolution and healing
- Pro-resolution factors
- Enamel matrix derivatives
- Growth factors e.g.: Bone morphogenetic proteins (BMPs). 
| Matrix Metalloproteinase Inhibition|| |
MMPs are a family of Zn + and Ca + dependent endopeptidases secreted or released by a variety of inflammatory cells. Transcription of MMP genes is up-regulated by pro-inflammatory cytokines. The role of inhibitors is particularly important because it is an imbalance between activated MMPs and their host-derived endogenous inhibitors that lead to breakdown of extracellular matrix during periodontitis. Compensating for the deficit in the naturally occurring inhibitors or tissue inhibitors of matrix metalloproteinases (TIMPs) to block or retard the proteolytic destruction of connective tissue is of therapeutic significance. 
Two types of inhibitors:
- Exogenous/natural inhibitors such as TIMP's and α2 macroglobulin
- Exogenous/synthetic inhibitors such as Zn 2+ and Ca 2+ -chelating agents, phosphorus containing peptides, sulfur based inhibitors, and hydroxamic acid inhibitors. 
| Tetracyclines|| |
Tetracycline with antibiotic activity consists of a tetracyclic naphthacene carboxamide ring system having a dimethylamine group at carbon 4 (C4) in ring "A" which is responsible for its antibacterial property. They are effective in treating periodontal diseases because their concentration in the gingival crevice is 2-10 times higher than in serum. Tetracycline's at low gingival crevicular fluid concentration 2-4 μg/ml and their ability to bind to tooth surface and bone enhance their activity at site of infection and are effective against many periodontal pathogens. In 1985, tetracycline had been discovered to have anticollagenolytic activity and was proposed as a host-modulating agent for periodontal treatment. 
| Sub Antimicrobial Dose of Doxycycline|| |
Doxycycline hyclate (Periostat): "Research is in My Blood" Dr. Lorne Golub, Developer of Periostat, received the ADA's Gold Medal Award for Excellence in Dental Research in 2006. Available as 20-mg capsule, prescribed twice daily for use. Approved by US Food and Drug Administrator (FDA), for the adjunctive treatment of periodontitis. It acts by suppression of the activity of collagenase, particularly that produced by polymorphonuclear neutrophils. It does not exhibit antimicrobial effects but can effectively lower MMP level  [Figure 3].
|Figure 3: Schematic of the periodontal pocket indicating the pleiotropic mechanisms by which doxycycline inhibits connective tissue breakdown. Down-regulation of destructive events in the periodontium by doxycycline results from modulation of a variety of different pro-inflammatory pathways|
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Goldberg et al. found that Combination of SDD plus low-dose flurbiprofen, together with repeated bouts of nonsurgical periodontal therapy, produces improvements in nonresponsive patients (refractory periodontitis).
| Sequencing Prescription with Periodontal Treatment|| |
- Not used as monotherapy, used as an adjunct to SRP
- Taken as 20 mg twice daily for 3 months and up to a maximum of 9 months
- Three months prescription fits well with the typical maintenance recall of 3 months. 
| Chemically Modified Tetracycline|| |
Golub et al. (1987),  discovered that the carbon 4 position side-chain was responsible for the antimicrobial activity of tetracyclines. In a series of experiments conducted later, the CMTs were produced by removing the dimethylamino group from the carbon 4 position of the A ring of the four-ringed (A, B, C, D) structure. The resulting compound, 4-de-dimethylamino tetracycline (CMT-1) did not have antimicrobial property, but the anticollagenase activity was retained both in vitro and in vivo [Figure 4].
The main advantage of CMTs over the conventional tetracyclines is that long-term systemic administration does not cause gastrointestinal toxicity and higher plasma concentrations can be obtained with less frequent administration regimens. 
| Inhibition of Arachidonic Acid Metabolite|| |
Nonsteroidal anti-inflammatory drugs
Another pathway involved in periodontal disease pathogenesis includes the synthesis and release of prostaglandins and other arachidonic acid metabolites within periodontal tissues. AA can be metabolized via the cyclooxygenase (CO) or lipoxygenase (LO) pathways. Two isoforms of Cox catalyze the synthesis of prostaglandins from AA namely Cox 1 and 2. The final products of the CO pathway include prostaglandins, prostacyclin, and thromboxane, whereas the end results of the LO pathway include leukotrienes and other hydroxyeicosatetraenoic acids. 
Nonsteroidal anti-inflammatory drugs inhibit the formation of prostaglandins, including PGE2, which is produced by a variety of resident and infiltrating cell types in the periodontium (including neutrophils, macrophage, fibroblast, and epithelial cells) in response to LPS. Recently, selective NSAIDs called coxibs (COX-2 inhibitors, Nimesulide) have been developed that selectively block the isoenzyme associated with inflammation (COX-2). 
| Pro-resolving Lipid Mediators|| |
Resolution-active or passive??!!
It is an active process involving biochemical circuits that actively biosynthesize local mediators within the resolution phase (Serhan 1997).
| Lipoxins|| |
Lipoxins are members of eicosanoid family produced by LO-mediated metabolism of arachidonic acid. They are generated late in the inflammation when a second LO interacts with LO produced earlier by other cell, and it will bind to specific receptors on neutrophils leading to resolution. These lipoxins prevent chemotaxis of neutrophils leading to apoptosis which further acts as a chemotactic agent for mononuclear phagocytes. In the presence of lipoxins, mononuclear phagocytes have a nondestructive (nonphlogistic) function. Thus, periodontal inflammation leading to tissue destruction is due to lack of resolution and pro-inflammatory stimuli.
| Resolvins and Protectins|| |
The term resolvins, resolution phase interaction products, was introduced to signify that the new structures are endogenous, local-acting mediators possessing potent anti-inflammatory, and immunoregulatory properties in the nanogram dosage in vivo. At the cellular level, these include reducing neutrophils infiltration, and regulating the cytokine-chemokine axis and reactive oxygen species, as well as lowering the magnitude of the inflammatory response. The protectin family and specifically the term neuro-protectin D1 when generated in the neural tissue were introduced, has very potent anti-inflammatory property and these mediators are considered to play a key role in many inflammatory diseases like Alzheimer's disease and periodontitis. 
| Triclosan|| |
Phenol derivative (2, 4, 4'- tricoloro-2'- hydroxyldiphenyl ether) is a nonionic antimicrobial agent used as mouthwashes and in toothpastes. It has both an antibacterial and anti-inflammatory agent actions:
- Acts on microbial cytoplasmic membrane inducing leakage of cellular constituents and thereby causing bacteriolysis
- Also inhibits cyclooxygenase and LO, and thus, may interfere with the production of AA metabolites. Use of dentifrice containing sodium fluoride (0.243%) and triclosan (0.3%) with 2.0% polyvinyl methyl ether maleic acid copolymer reduced the frequency of deep periodontal pockets and the number of sites exhibiting attachment and bone loss in patients deemed highly susceptible to periodontitis. 
| Nutrients|| |
The damage mediated by reactive oxygen species can be mitigated by antioxidants through three separate mechanisms namely: Scavengers of free radicals as they are formed, sequestering transition metal ions, catalyzing the formation of other molecules. Nutrients, which include major extracellular antioxidants like Vitamin C, Vitamin E, carotenoids, reduced glutathione, and omega 3 fatty acids act through these mechanisms. 
Bodet et al., 2007  demonstrated that cranberry juice contains molecules (A-type cranberry proanthocyanidins) that inhibit MMPs, IL-6, IL-8, and prostaglandin E production by LPS-activated gingival fibroblasts, and hence, show potential of being used as a novel host-modulating agent to inhibit tissue destruction during periodontitis.
| Modulation of Bone Metabolism|| |
Bisphosphonates were introduced in 1990 for the treatment of osteoporosis and osteolytic tumors. They are nonbiodegradable analogs of pyrophosphate that have a high affinity for calcium phosphate crystals. They have the ability to modulate the bone loss and prevent bone resorption, hence known as bone-sparing agents. Alendronate has been evaluated in ligature-induced periodontitis models and assessed for changes in bone density. A pilot human clinical study was performed to assess the efficacy of alendronate in slowing alveolar bone loss associated with periodontitis. Limitations of these drugs on prolonged use may lead to inhibition of bone mineralization and subsequent osteomalacia, change in white blood cell counts, and jaw necrosis [Table 1] and [Table 2]. 
|Table 1: Mechanism of action of bisphosphonate at tissue, cellular, and molecular levels |
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|Table 2: Treatment recommendations for osteoporosis patients receiving oral bisphosphonates |
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| Estrogen and Selective Estrogen Receptor Modulators|| |
Estrogen deficiency is associated with an increase in bone resorption in females with osteoclast formation and activity and reduced osteoclast apoptosis. Treatment with estrogens clearly inhibit bone loss as well as bone turnover and increase bone mineral density. The effect of steroid hormones as metabolic mediators of the expression of cytokines may be a reasonable explanation for the protective effect of estrogen supplementation against periodontal disease. Selective estrogen receptor modulators appear to offer many of the benefits of estrogen with minimal adverse effects. Raloxifene is the first drug in this class approved for the treatment of osteoporosis. ,
| Antiintegrins|| |
An early key event in the bone resorption process is the attachment of the osteoclast to the bone matrix. This matrix attachment is mediated by integrin primarily μvb3 and result in the intimate contact of the osteoclast with the matrix to be resorbed and formation of the sealing zone that enables the osteoclast to isolate a microenvironment beneath it to facilitate resorption. Blocking the adhesion of osteoclasts to their target matrix through the use of agents that disrupt integrins has been reported to inhibit bone resorption and may provide viable option after a clinical investigation. 
| Regulation of Immune and Inflammatory Response|| |
Suppressing pro-inflammatory cytokines: IL-1 and TNF-α receptor antagonist.
Pro-inflammatory (e.g., IL-1α, IL-1β, IL-6, TNF-α, IFN-g, etc.) and anti-inflammatory cytokines (IL-4, IL-10, etc.) hold a great potential for controlling the adverse effects of the host immune response, consequently HMT against cytokines (cytokine therapy) may prove to be an effective strategy for treating periodontal diseases. 
These therapies aim at:
- Antagonizing the pro-inflammatory cytokines via
Cytokine receptor antagonist: Binds to the receptor present on the target cell and prevents the cytokine from binding to the target cell. e.g. IL-1 receptor antagonist, which is commercially available as Kineret (Anakinra).
- Anticytokine antibodies: Some of the anticytokine antibodies currently available are:
- Anti-TNF-α antibody: Adalimumab, Certolizumab pegol, Golimumab, etc.
- Anti-IL-6 antibody: Tocilizumab
- Anti-IL-15 antibody: AMG714
- Anti-IL-12 and IL-23 antibody: Ustekinumab
- Anti-IL-17 antibody: AIN457
- Soluble cytokine receptors: Binds to the cytokines in solution and prevents signaling, e.g. sIL-1R, sTNF-R, and sIL-6R are the soluble receptors against IL-1β, TNF-α, and IL-6, respectively. 
| Recombinant Anti-inflammatory Cytokine Administration|| |
Martuscelli et al.  demonstrated that subcutaneous injections of recombinant human IL-11 (rhIL-11: Anti-inflammatory cytokine) were able to slow the progression of attachment and radiographic alveolar bone loss in a ligature-induced beagle dog model.
| Nitric Oxide|| |
Nitric oxide (NO) is a free radical with important physiological functions including cardiovascular system, nervous system, and immune homeostasis. NO activates MMP in cultured chondrocytes. Function as a second messenger mediating the effects of the pro-inflammatory cytokine IL-1β in articular chondrocytes. High local cover of NO and peroxynitrite (product of NO + superoxide) are cytotoxic to bacteria, fungi protozoa, and tumor cells may also cause deleterious host effects such as DNA damage, lipid peroxidation, protein damage, and stimulation of inflammatory cytokines. 
| Nuclear Factor Kappa B|| |
It is an important transcription factor complex that appears to play a fundamental role in regulating inflammation. Occurs inactively in the cytoplasm of most inflammatory cells but is activated and released in response to pro-inflammatory stimuli. Free nuclear factor kappa B (NFkB) diffuses across the nuclear membrane, binds to DNA, and stimulates cytokine gene expression and release. 
| Antagonist for Endothelial Cell Adhesion Molecules|| |
E-selectin and intercellular adhesion molecule-1 expressed on endothelial cell membranes that are responsible for the rolling and tethering of leukocytes during extravagation events. Agents such as tepoxalin, sodium cromoglycate, BMS-190394, and Kappa opioid PD 117302 show promising results in inflammation models. 
| Disrupting Inflammatory Cell-signaling Pathways|| |
To inhibit the production of pro-inflammatory cytokines and/or stimulate anti-inflammatory cytokine production. Cell signaling pathways like mitogen-activated protein kinase, NFkB, Janus kinase/signal transducers and activators of transcription, and RANK-RANKL-osteoprotegerin (OPG) pathways are dependent on a number of signaling-intermediate molecules for its uninterrupted functioning. Targeting these pathways or the intermediate signaling molecules for their blockade with HMT may be more effective than targeting specific cytokines. 
Lima et al.  further demonstrated the protective role of pentoxifylline, a methylxanthine derivative, in experimental periodontitis as an inhibitor of cytokine synthesis, mainly TNF.
Jin et al.  demonstrated that the systemic delivery of OPG-Fc fusion protein inhibits alveolar bone resorption in experimental periodontitis, supporting the fact that RANKL inhibition may represent an important therapeutic strategy for the prevention of progressive alveolar bone loss. Studies to date have indicated that RANKL inhibitors, such as a fully human monoclonal antibody that specifically targets RANKL currently available as denosumab can lead to increased bone mineral density and decreased bone resorption.
| Periodontal Vaccines|| |
Vaccination is the induction of immunity by injecting a dead or attenuated form of a pathogen. The key features of a successful vaccine are safety, effectiveness, stability, a long shelf life, and relatively low cost.
Types of periodontal immunization:
- Active immunization
- Passive immunization
- Genetic immunization.
The organism that is targeted the most using vaccines is P. gingivalis.
The virulence factors of P. gingivalis which have been used as subunits for the development of active immunization are:
- Outer membrane protein,
- Fimbriae and
- Heat shock protein.
Some genes from periodontopathic bacterial are cloned.
E.g. A. actinomycetemcomitans Y 4 antigen, P. gingivalis (fimbrial subunit proteins) strains, and Treponema denticola surface antigen (tdpA). These genes could be used as a vaccine to protect against periodontitis. 
| Other Host Modulatory Therapies|| |
Probiotics have demonstrated significant potential as therapeutic options for a variety of disease. Recently, Teughels et al.  explored the use of probiotics in influencing the periodontal microbiota and periodontal health, and concluded that probiotics might offer opportunities to manipulate the oral microbiota, and periodontal health by either direct microbiological interactions or by immunomodulatory interactions.
| Locally Administered Host Modulation Therapy|| |
Enamel matrix proteins
Enamel matrix derivative is now commercially available for the treatment of periodontal defects as Emdogain which has received FDA approval. Enamel matrix proteins (EMD) initiates periodontal regeneration through recruitment of cementoblasts to the root surface and stimulates these to form root-cementum, which will thereafter secondarily lead to regeneration of periodontal fibers and alveolar bone. The above-mentioned actions of EMD justify its role as a host modulating agent. 
Bone morphogenetic protein
One BMP guides modulation and differentiation of mesenchymal cells into bone and bone marrow cells. Absorbable collagen sponge (ACS) containing rhBMP-2 has been approved for clinical use in certain oral surgery procedures, including localized alveolar ridge augmentation for defects associated with extraction sockets. These applications are the third FDA-approved indication for Bone Graft. These ACS release the protein over time in the location where it is implanted and provides a scaffold on which new bone can grow. As the graft site heals, the ACS is absorbed and replaced by bone. 
Platelet derived growth factor
FDA has approved growth-factor enhanced matrix, GEM 21S which is a combination of a bioactive highly purified rh platelet derived growth factor (PDGF)-BB with an osteoconductive bone matrix. PDGF, as a host modulating agent can increase chemotaxis of neutrophils and monocytes, stimulate fibroblasts proliferation and extracellular matrix synthesis, increase proliferation and differentiation of endothelial cells, stimulate proliferation of mesenchymal progenitor cells, and differentiation of fibroblasts. 
| Conclusion|| |
Host response modulation has emerged as a valid treatment concept for the management of periodontal disease and represents a significant step forward for clinicians and patients. There are situations in which conventional therapy does not always achieve the diseased clinical outcome. In these instances and for specific groups of periodontal disease susceptible individuals, the use of HMT in conjunction with antibiofilm treatments may prove to be advantageous. As methods that modulate the host response become available, they may be useful as adjunctive therapies for a variety of clinical situations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]