Host modulation therapeutic agents in periodontics

As already discussed in the previous chapters, the primary etiology of periodontal diseases is bacterial infection 1. In addition to bacterial etiology, the progression of periodontal diseases is adversely influenced by a number of risk factors and risk indicators like diabetes, gender, age, hereditary factors and smoking 2. Traditional treatments focused on reducing the bacterial load through scaling and root planning, but they were not effective in every patient. Löe et al. (1986) 3 in their study on Sri Lankan tea workers demonstrated that not all individuals have the same response to similar amounts of plaque accumulation.

Definition

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.

The purpose of HMT is to restore the balance, on one hand, between pro-inflammatory and anti-inflammatory mediators and on the other hand between destructive enzymes and their inhibitors. They can be systemically administered or locally delivered and used as adjuncts to scaling and root planning 4.

Pathogenesis of periodontal disease

Presently, the models of periodontal disease progression 5, 6 suggest that a major component of connective tissue destruction associated with periodontal disease is the result of activation of the host’s immuno-inflammatory response to the bacterial challenge. The underlying biological mechanisms of this response are characterized by the expression of endothelial cell and intercellular adhesion molecules and by the production of host-derived inflammatory mediators, including, cytokines and lipids by neutrophils, monocytes, lymphocytes and fibroblasts.

Balance of inflammatory mediators in periodontal health and disease

The balance between inflammatory mediators and their counter-regulatory molecules is crucial for determining the outcome of the immuno-inflammatory pathology of periodontal diseases. In the case of stable gingivitis lesion, the pro- and anti-inflammatory response is supposed to be in balance, whereas the response is skewed towards the predominance of pro-inflammatory reactivity in progressive periodontitis lesion. In the context of tissue destruction, cytokines such as interleukin (IL)-1, IL-6 and IL-18 are likely to be important, as are their regulating cytokines IL-10 and IL-11.

As present data suggest that periodontal diseases have got a multi-factorial etiology, the risk factors are equally important in the final outcome of the disease progression. Figure 14.1 describes the balance between the various factors favoring periodontal health and disease.

Figure 14.1  balance between the various factors favoring periodontal health and disease.

Balance of inflammatory mediators in periodontal health and disease

 

Host modulation therapeutic agents

Before we go through the therapeutic agents used in host modulation, let us first try to understand the steps where these agents modulate the host response. Figure 14.2 demonstrates various steps where therapeutic agents modulate the host response and thus the final outcome of the periodontal disease.

Figure 14.2  various steps where therapeutic agents modulate the host response and thus the final outcome of the periodontal disease.

Various steps where therapeutic agents modulate the host response and thus the final outcome of the periodontal disease.

Classification of host modulation therapeutics

  1. Modulation of the immune response.
    1. Pro-inflammatory cytokine inhibition
    2. Modulation of matrix metalloproteinase (MMP) activities
  2. Modulation of arachidonic acid metabolites
    1. Nonsteroidal anti-inflammatory drugs
    2. Lipoxins and resolvins
  3. Modulation of bone remodeling
    1. Anti-Inflammatory agents
    2. Bisphosphonates
    3. Chemically modified tetracyclines
    4. Hormone replacement therapy for post-menopause women.
  1. Host modulation by promoting periodontal regeneration
  2. Modulation of nitric oxide synthase (NOS) activity
  3. Modulation of cell signaling pathways in periodontal diseases

Modulation of the immune response

Pro-inflammatory cytokine inhibition:

Many studies have indicated that the biological activity of a variety of cytokines may be directly relevant to periodontal destruction 7, 8. IL-1, IL-6, and tumor necrosis factor (TNF) have all been found to be significantly elevated in diseased periodontal sites as compared to healthy or inactive sites 9-12. Cytokines have a synergistic effect. Acting together pro-inflammatory cytokines amplify the inflammatory condition. For example, IL-1β has synergistic activity with TNF-α or lymphotoxin in stimulating bone resorption 13. Blocking TNF-α has been proven to inhibit osteoclast formation effectively 14. As already explained in the previous sections, the balance between the pro and anti-inflammatory cytokines is crucial in the periodontal health and disease. So, we can possibly regulate the disease progression by regulating the balance of anti-/pro-inflammatory cytokines, matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) and receptor activator of nuclear factor-κB ligand (RANKL)/osteoprogerin (OPG). Imbalances between these mediators in the periodontal tissues are a major cause of periodontal destruction 15-17.

Pentoxifylline (PTX) is a …………………….

123

Periobasics: A Text Book of Periodontics and Implantology
For India Users:
Buy Now
For International Users:


Modulation of matrix metalloproteinase (MMP) activities:

The activity of MMPs can be modulated by various ways which include, modulation of the production of MMPs, blocking activation of the proenzyme, blocking the activity of the enzyme, and activating MMP inhibitors 22. The MMPs are a family of zinc- and calcium-dependent endopeptidases secreted or released by a variety of infiltrating cells (i.e., neutrophils and macrophages) and resident cells (i.e., fibroblasts, epithelial cells, osteoblasts, and osteoclasts) found in the periodontium 23. MMPs include collagenases, gelatinases, and metallo-elastases. MMPs have been strongly associated with periodontitis 24-28, and excellent reviews have been published discussing the role of MMPs in periodontal diseases 22, 29-31. For more details please read ‘The Matrix Metalloproteinases’.

While experimenting on germ-free diabetic rats Golub et al. (1983, 1994) 32, 33 discovered the anti-collagenase activity of tetracyclines. Ten different chemically modified tetracyclines (CMTs) have been developed, 9 of which inhibit MMPs and do not possess antimicrobial properties 23. In further studies using these different tetracyclines, Golub et al 34 (1985) reported that……………

123

Periobasics: A Text Book of Periodontics and Implantology
For India Users:
Buy Now
For International Users:


Periostat:

Periostat is a formulation containing a sub-antimicrobial dose of Doxycycline (SDD) (Doxycycline Hyclate 20 mg; Periostat, CollaGenex, Pharmaceuticals Newton PA) which is FDA approved and ADA accepted in 1998. It is indicated as an adjunct to scaling and root planning (SRP) taken twice daily for a period of 3-9 months in the treatment of chronic periodontitis. 20 mg dose of Doxycycline has been reported not to exhibit antimicrobial effects, but can effectively lower MMP levels 36. Various effects of sub-antimicrobial dose of Doxycycline on host response have been enumerated in Table 14.1.

 

Figure: 14.3 Commercially available doxycycline 20 mg

periostat

Table: 14.1 

Mechanism of action of doxycycline in host modulation
.
Direct inhibition of active MMPs by cation chelation (dependent on Ca2+- and Zn2+-binding properties).
Inhibits oxidative activation of latent MMPs (independent of cation-binding properties)
Down regulates expression of key inflammatory cytokines (interleukin-1, interleukin-6 and tumor necrosis factor-α) and prostaglandin E2.
Scavenges and inhibits production of reactive oxygen species produced by neutrophils.
Inhibits MMPs and reactive oxygen species thereby protecting α1-proteinase inhibitor, and thus indirectly reducing tissue proteinase activity.
Stimulates fibroblast collagen production
Reduces osteoclast activity and bone resorption.
Inhibits osteoclast MMPs.

A lot of research work has been done on SDD. Studies done on the gingival crevicular fluid found an increase in the level of transforming growth factor-β1 in the adjunctive low-dose doxycycline test group as compared to the control group, which received only scaling and root planing (SRP) and a placebo 38-40. A combination of low-dose doxycycline and NSAIDs has been found to suppress MMP activity more than low-dose doxycycline alone 41.

A meta-analysis 42 of 6 selected clinical studies comparing long-term systemic SDD (20 mg bid doxycycline) to a placebo control in periodontal patients showed a statistically significant adjunctive benefit of SDD + SRP on clinical attachment levels and probing depth, in both 4 to 6 mm and ≥ 7 mm pocket depth categories. Bleeding on probing was not assessed in the meta-analysis but, in general, SDD did not improve this parameter when compared to placebo. No significant adverse effects were reported in any of the studies. As far as bacterial resistance to the drug therapy is concerned, the resistance associated with low-dose doxycycline therapy has not been seen 43.

Modulation of arachidonic acid metabolites

Nonsteroidal anti-inflammatory Drugs:

The fact that NSAIDs can suppress alveolar bone resorption suggests that the synthesis of arachidonic acid metabolites may represent a critical regulatory pathway for potentially blocking periodontal disease progression activity 44. In arachidonic acid metabolism, the cyclooxygenase pathway produces prostaglandins, prostacyclin, and thromboxane, called prostanoids. Some prostanoids have pro-inflammatory properties and have been associated with the destructive process in the inflammatory diseases. In periodontal diseases, Prostaglandin E2 (PGE2) has been extensively correlated to inflammation and bone resorption 5.

Multiple NSAIDs, including indomethacin 45, flurbiprofen 46, ibuprofen 47, naproxen 48, meclofenamic acid 49, and piroxicam 50 have demonstrated the ability to inhibit gingivitis 50 and progression of periodontitis in both ligature-induced 45, 51 and naturally occurring periodontal disease in animal models 46- 48 .

Lipoxins and resolvins:

Bacteria and their products like lipopolysaccharides (LPS) initiate an inflammatory response when they are countered by the protective host response. Many mediators produced by arachidonic acid pathway, including prostanoids, leukotrienes, and related compounds, play important roles in the initiation and progression of inflammation and are thus termed as “pro-inflammatory mediators” 52, 53. In addition to the pro-inflammatory mediators, “anti-inflammatory mediators” are also produced during these interactions. These include lipoxins, aspirin-triggered 15-epi-lipoxins (ATLs), resolvins, docosatrienes, and neuroprotectins. Lipoxins are……………………….

123

Periobasics: A Text Book of Periodontics and Implantology
For India Users:
Buy Now
For International Users:


As these are a new class of endogenous mediators that are anti-inflammatory or serve for the “pro-resolution” of inflammation, research work is going on in this field to explore the future possibilities of their clinical use.

Modulation of bone remodeling:

Anti-Inflammatory Agents:

Arachidonic acid metabolites are pro-inflammatory medi­ators that have been implicated in a variety of bone resorptive processes including chronic periodontitis 56. These mediators can be inhibited by NSAIDs, which include various drugs such as aspirin, ibuprofen, ketorolac, flurbiprofen, naproxen, etc. They inhibit the enzyme cyclooxyge­nase, thereby preventing the production of arachidonic acid metabolites which are involved in bone resorption.

Bisphosphonates:

Periodontitis is characterized by the alveolar bone loss. One of the therapeutic modality of host modulation is to stop the alveolar bone resorption. Bisphosphonates are widely used in the management of systemic metabolic bone disorders such as osteoporosis and Paget’s disease. They have a primary indication of inhibiting bone resorption and thereby maintaining bone density 57. They are used widely in conditions such as neoplastic hypercalcemia, multiple myeloma, and bone metastases secondary to breast and prostate cancer, suggesting a direct antitumor effect of bisphosphonates.

Chemical structure:

Chemically bisphosphonates are pyrophosphate analogs characterized by two C-P bonds (Figure 14.4). They are identified by a common ending in their generic names (“……….. dronate”). These drugs can be subdivided into the nitrogen-containing bisphosphonates and non-nitrogen-containing bisphosphonates 58. Small changes in the structure of the bisphosphonates can lead to extensive alterations in their physicochemical, biological, therapeutic, and toxicological characteristics.

Figure 14.4 Structure of bisphosphonates

Generations of bisphosphonates:

Bisphosphonates are classified into three generations according to the R1 and R2 groups present in their chemical structure (Table 14.2).

Table 14.2 Generations of bisphosphonates

Bisphosphonates are classified into three generations according to the R1 and R2 groups present in their chemical structure.

1st Generation

(Non- Nitrogen Containing)

2nd Generation(R2 group contains nitrogen in form of a primary amino group)

3rd Generations

(R2 group contains nitrogen but within a heterocyclic group)

  • Etidronate
  • Clodronate
  • Alendronate
  • Pamidronate

(10-1000 more potent than the 1st generations)

  • Risedronate
  • Ibandronate
  • Zoledronic Acid

(10,000- 100,000 more potent than 1st generation). 

 

 

Physicochemical effects:

Bisphosphonates work by inhibiting the precipitation of calcium phosphate even at very low concentration 59. They also slow down the dissolution of these crystals 60. All these effects appear to be related to the marked affinity of these compounds for the solid-phase calcium phosphate to which they bind 61. These compounds inhibit osteoclastic activity by blocking acidification by local release and represent a class of chemical structures related to pyrophosphates 62. They also downregulate levels of several MMPs including MMP-3, MMP-8, and MMP-13 from human periodontal ligament cells 63. The effects of bisphosphonates at tissue level, cellular level, and molecular level are summarized in Table 14.3.

Table 14.3 Effects of bisphosphonates at tissue level, cellular level and molecular level.

Tissue level

Cellular level

Molecular level 

↓sed Bone turnover due to ↓sed Bone resorption.
↓sed Number of new bone multicellular units.
Net positive whole body bone balance.
↓sed Osteoclast recruitment
↑sed Osteoclast apoptosis
↓sed Osteoclast adhesion
↓sed Depth of resorption site
↓sed release of cytokines by macrophages.
↑sed Osteoblast differentiation and number.
Inhibit mevalonate pathway (that result in perturbed cell activity and induction of apoptosis).
↓sed Post-translational prenylation of GTP- bonding proteins.

 

Adverse effects:

A serious adverse effect of bisphosphonates that has substantial dental implications is osteonecrosis of the jaws (Table..); other bones in the skeleton do not appear to be involved 64. Good dental hygiene reduces the risk of osteonecrosis.

Know more……Bisphosphonate-related osteonecrosis of the jaw (BRONJ):All the patients who are undergoing bisphosphonate related treatment for bony defects or implant therapy should be informed about all the complications associated with bisphosphonate treatment. Advisory Task Force on Bisphosphonate-Related Ostenonecrosis of the Jaws, 2007 has proposed following staging categories and treatment guidelines regarding BRONJ,

BRONJ Staging

Treatment Strategies

At risk category: No apparent exposed/necrotic bone in patients who have been treated with either oral or IV bisphosphonates No treatment indicated
Patient education
Stage 1: Exposed/necrotic bone in patients who are asymptomatic and have no evidence of infection Antibacterial mouth rinse
Clinical follow-up on a quarterly basis
Patient education and review of indications for continued bisphosphonate therapy
Stage 2: Exposed/necrotic bone associated with infection as evidenced by pain and erythema in the region of the exposed bone with or without purulent drainage Symptomatic treatment with broad spectrum oral antibiotics, e.g. penicillin, cephalexin, clindamycin, or first generation fluoroquinolone
Oral antibacterial mouth rinse
Pain control
Only superficial debridements to relieve soft tissue irritation
Stage 3: Exposed/necrotic bone in patients with pain, infection, and one or more of the following: pathologic fracture, extraoral fistula, or osteolysis extending to the inferior border Antibacterial mouth rinse
Antibiotic therapy and pain control
Surgical debridement/resection for longer term palliation of infection and pain

 

Recent research:

A lot of research work has been done on bisphosphonates and periodontitis. Sodium alendronate treatment in experimental periodontitis in Wistar rats was studied and the results showed that sodium alendronate preserves alveolar bone resorption and has anti-inflammatory and antibacterial activities in experimental periodontitis 65. MMP Inhibition and down-regulation by bisphosphonates has also been demonstrated in one study, which observed the inhibition of MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 by clodronate, alendronate, pamidronate, zoledronate, and inordinate 66.

A study was done to investigate the effects of oral alendronate treatment on radiological and clinical measurements of periodontal disease in postmenopausal women without hormone replacement therapy. Results demonstrated that alendronate treatment improved the periodontal status and bone turnover in postmenopausal women 67.

Recent studies have demonstrated that osseointegration of titanium implants can be significantly reinforced with a nanostructure treated with anodic oxidation and heat treatment. An animal experimental study was done on a machine-turned, anodized + heat-treated and anodized + heat treated + bisphosphonate-treated implants. Results showed that surface loading with bisphosphonates significantly improved the degree of osseointegration of titanium implants with a nanostructure 68.

Chemically Modified Tetracyclines (CMTs):

As it is well established that CMTs inhibit the MMPs so are indirectly involved in inhibition of bone resorption in periodontal diseases.

Hormone replacement therapy for post-menopause women:

The endocrine system plays an important role in the homeostasis of the periodontium 69. Osteoporosis, which is defined as a systemic condition characterized by a decrease in the bone mineral density by at least 2.5 times the normal value in a healthy young female, is a major health problem in postmenopausal women 70. It is a major cause of morbidity and mortality in post menopause women. The research work clearly indicates that low estrogen production after menopause is associated with increased production of IL-1, IL-6, IL-8, IL-10, TNF-α, granulocyte colony-stimulating factor, and granulocyte-macrophage-colony-stimulating factor, which stimulates mature osteoclasts, modulates bone cell proliferation and induces resorption of both skeletal and alveolar bone 71, 72. The American Academy of Periodontology considers osteoporosis to be a risk factor for periodontal disease 73.

Clinical changes in the periodontal tissues during menopause and post-menopause:

  • Reduction in epithelial keratinization 74
  • A reduction in salivary gland flow 75
  • Drying of the oral tissues 76
  • Redness and abnormal paleness of the gingival tissues 76
  • Bleeding on probing and brushing 76
  • Taste sensation may change, causing frequent complaints of a metallic taste 77

Radiographic changes in the periodontal tissues during menopause and postmenopause:

  • Reduced bone mineral content in the jaws 78, 79.

Hormone replacement therapy (HRT) is used to relieve these symptoms and improve the quality of life of peri- or post-menopausal women 80, 81. Many studies have suggested that using HRT in post-menopausal women can decrease the periodontal destruction 79, 82 and increase tooth retention 83.

Effects of HRT on the periodontal tissues:

  • Protection against tooth loss 83
  • Reduction in gingival bleeding 84
  • Reduction in the risk of edentulism 85

Host Modulation by Promoting Periodontal Regeneration:

Root surface conditioning, growth factors, and cytokines can be used to promote periodontal regeneration. Growth factors and hormones, including platelet-rich plasma (PRP), bone morphogenic proteins (BMPs), platelet-derived growth factor (PDGF), parathyroid hormone (PTH), and enamel matrix derivatives (EMD) have shown promise in enhancing regeneration, although their long-term predictability remains questionable, and their anticipated benefits are moderate 86, 87. In 1976, Melcher presented the concept of “compartmentalization,” in which the connective tissues of the periodontium were divided into four compartments: the lamina propria of the gingiva (gingival corium), the periodontal ligament (PDL), the cementum, and the alveolar bone 88. Since then a lot of research has been done on periodontal regeneration. Regeneration has been broadly divided into two categories; graft associated and non-graft associated. For details, read ‘Periodontal Regeneration’.

Modulation of nitric oxide synthase (NOS) activity:

Nitric oxide (NO) is a free radical involved in host defense that can be toxic when present in high concentrations and it has been implicated in a variety of inflammatory conditions. NO is produced by a wide variety of cells and appears to be an important regulator of various physiologic processes in both animals and humans 89. NO imbalances have been noted in a variety of chronic infectious and inflammatory conditions, including, periodontal disease 90-92.

NO is generated within biologic tissues via the enzymatic conversion of L-arginine to L-citrulline by NOS. Nitric oxide synthase (NOS) exists in the body in three distinct isoforms: neuronal (nNOS or NOS-I), inducible (iNOS or NOS-II) and endothelial NOS (eNOS or NOS-III) 93.

NO has a critical role in the regulation of vascular tone, smooth muscle proliferation, angiogenesis,  coagulation, mitochondrial energy generation, neurotransmission, immunity, cell survival, and wound healing 94-97. The importance of NO in bone formation and remodeling has been highlighted from the observations of defective bone formation, volume, turnover, and osteoblast function in eNOS and iNOS deficient mice 98-100.

The role of NO in periodontal diseases has been well investigated. LPS and other antigenic substances from putative periodontal pathogens such as Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Prevotella nigrescens, and Fusobacterium nucleatum have been shown to induce the iNOS expression and NO production in murine macrophages 101-104.

It has been demonstrated that iNOS expression and activity is induced in gingival fibroblasts and neutrophils, following the stimulation by periodontal pathogens, cytokines, and other inflammatory mediators 105. Along with this, neutrophils isolated from localized aggressive periodontitis patients were shown to display increased iNOS activity and subsequent chemotactic defects 106……………

123123

Periobasics: A Text Book of Periodontics and Implantology
For India Users:
Buy Now
For International Users:


Modulation of cell signaling pathways in periodontal diseases:

As we know that bacterial biofilm present in the gingival sulcus around the tooth is a source of various bacterial components and products, which initiate the host response. First of all the innate immune system counters the infection, but when not controlled, the acquired immune system is activated. The invader is recognized by the antigen presenting cells and presented to T-cells by MHC-I or MHC-II, depending on which helper or cytotoxic-T-cell mediated immune response is generated. Within 3-4 days a robust inflammatory response is generated, which initiates the connective tissue destruction. Now this activation is done by various cellular signaling mechanisms, which leads to the synthesis of various cytokines and other inflammatory chemical mediators. When a signal is generated, it travels through the cytoplasm and reaches the nucleus, and ultimately the pattern of gene expression is altered by transcriptional and post-transcriptional mechanisms. Signal transduction depends on receptor-ligand interactions, which usually involves some modification on the cytoplasmic proteins associated with these receptors. The most common modification associated with signal transduction is phosphorylation of specific amino acid residues by kinases, which induces a conformational change in the tri-dimensional structure of the protein. In the process of intracellular signaling, energy is transferred at every step which modulates the biological activity of the proteins involved. In periodontal disease, the most important pathways include the mitogen-activated protein kinase (MAPK), nuclear factor kappa B (NF-κB) and Janus tyrosine kinase-signal transducer and activator of transcription (JAK/STAT) 110, 111.

MAPK pathway:

The MAP kinases are a large family of protein kinases which are involved in cellular signaling pathways in various biological processes. These are involved in signal transduction of extracellular hormones, growth factors, and cytokines 112, 113. MAPKs are further divided into three classes: extracellular-regulated kinases (ERK-1/-2), c-Jun N-terminal activated kinases (JNK), and p38. During inflammation, MAPK pathways (particularly, p38) are involved in the increased expression of various cytokine genes by modulation of both transcriptional and post-transcriptional mechanisms. Studies have demonstrated that inhibition of JNK and ERK pathways may effectively inhibit the production of pro-inflammatory mediators 114, 115. Furthermore, the MAPK inhibitors have been shown to be capable of reducing inflammation in inflammatory conditions like rheumatoid arthritis and periodontal disease 116-119.

Studies have shown that the inhibition of these signaling pathways can lead to the reduction in the synthesis of pro-inflammatory cytokines. These findings have been demonstrated in patients with inflammatory diseases such as rheumatoid arthritis and periodontal disease 116-121. However, more human trials are required to prove their efficacy as host modulation agents in periodontal diseases.

NF-κB pathway:

The NF-κB is a family of transcription factors involved in various signal transduction pathways involved in both adaptive and innate immune responses. The NF-κB family consists of five members: REL-a (p65), NF-κB1 (p50; p105), NF-κB2 (p52; p100), c-REL and REL-b 122. The NF-κB pathway is activated when a large number of pro-inflammatory mediators, such as bacterial LPS, TNF-α, IL-1, MMPs, COX2 and inducible nitric oxide synthase (iNOS) are present in tissue 123, 124. It has been demonstrated that periodontal pathogens like P. gingivalis and others also activate NF-κB in periodontal tissues 125.

As already stated, the NF-κB family consists of five members. Except for REL-b, all other members join to form homodimers or heterodimers to produce NF-κB transcription factors. During inflammatory reactions, the most common heterodimer formed is of p50 and p65. This heterodimer binds to NF-κB 5′-3′ site and to activate or repress target gene transcription 126, 127. The NF-κB is also involved in the TRL activation pathway. Agents that prevent degradation of NF-κB inhibitors have been investigated to inhibit the NF-κB pathway 128. However, these strategies are still under investigation to be used clinically.

JAK/STAT pathway:

The JAK/STAT pathway is involved in signal transduction of interleukins, interferons, epidermal growth factor, growth hormone, erythropoietin and other mediators 129. In periodontitis, this pathway is the major mechanism of signal transduction for cytokines, including IFN-γ, TNF-α, IL-1 IL-4, IL-6, and IL-10 120, 130, 131. Cytokines and interferons exert their role in the regulation of immune response by activating the enzymes, JAK or Janus kinases. These enzymes are associated with the cytoplasmic portion of the transmembrane receptors 132. These enzymes further activate proteins known as STATs (STAT1-4, 5a, 5b, and 6) in the cellular cytoplasm. STATs upon phosphorylation may form homo- or heterodimers; which enables them to enter the nucleus, where they can regulate gene transcription 133. Since experimental studies have shown JAK deficiency to be lethal, targeting these kinases for host response modulation does not seem to be useful 134, 135. Presently, no literature is available regarding the use of STAT inhibitors and the potential beneficial role in reducing periodontal inflammation.

Limitations of host modulation therapy

In the above discussion, we studied various therapeutic modalities which have been investigated and used for host response modulation. However, presently there are many li0mitations of HMT. The first limitation is regarding the duration of therapy. For most of the host modulation agents, the duration for which these can be safely given is not well established. For SDD, twice a day as an adjunct for the treatment of chronic periodontitis both in short term duration of 1 – 3 months and longer duration of up to 9 months showed more improved and predictable treatment outcomes without the emergence of adverse effects of doxycycline and any alterations in the subgingival microflora 136. However, for many other host modulation agents, the clinical data for their long term use is insufficient to authenticate the safety of their use.

The second limitation associated with the use of host modulation agents is the side effects associated with them. As already discussed, use of bisphosphonates may cause osteonecrosis in some patients. The local and systemic side effects of many other host modulation agents are still not clear because of lack of long term studies on them.

Conclusion

The initiation and progression of periodontal diseases are the result of interactions between periodontopathogenic microorganisms and host response. In some clinical situations (systemically compromised patient, smokers, genetically predisposed patients), the conventional periodontal therapy does not always achieve the desired clinical outcome. Furthermore, cases which are refractory to conventional treatment and patients in whom surgical approach is not possible because of medical risk factors or age, the host modulation therapy is desirable along with the conventional anti-biofilm therapy. However, on many of the host modulation agents, long-term clinical trials still need to be done to authenticate their efficacious, safe and long term use on patients.

Periobasics: A Text Book of Periodontics and Implantology
For India Users:
Buy Now
For International Users:


References:

References available on the hard copy of the website

Periobasics: A textbook of periodontics and implantology

Leave a Reply

You must be logged in to post a comment.