JICDRO is a UGC approved journal (Journal no. 63927)

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Year : 2021  |  Volume : 13  |  Issue : 2  |  Page : 93-100

Comprehensive evaluation of adverse effects of host modulatory agents: A critical review

Department of Periodontology and Oral Implantology, Luxmi Bai Institute of Dental Sciences and Hospital, Patiala, Punjab, India

Date of Submission23-Jan-2021
Date of Acceptance03-Jul-2021
Date of Web Publication17-Jan-2022

Correspondence Address:
Dr. Ashutosh Nirola
Department of Periodontology and Oral Implantology, Luxmi Bai Institute of Dental Sciences and Hospital, Patiala, Punjab
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jicdro.jicdro_3_21

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Recent advances in study of inflammatory pathways are bringing up new pathways of understanding regarding the bone loss and tissue destruction related to periodontitis. This knowledge, along with the development of novel drugs like host modulatory agents that can inhibit bone loss/destruction, provides us with opportunities to manage not only soft tissue inflammation but also the destructive bone loss occurring during periodontitis. The use of such agents as an adjunct to conventional periodontal therapy, not only minimizes the current periodontal disease severity and improves treatment prognosis, but also reduces future susceptibility to periodontal disease. But there are certain adverse effects secondary to these agents and thus this literature review sheds light on some of these adverse reactions which are known to be caused by these novel drugs

Keywords: Adverse, bisphosphonates, doxycycline, effects, host, modulation, nonsteroidal anti-inflammatory drugs, response

How to cite this article:
Nirola A, Batra P, Bali BK. Comprehensive evaluation of adverse effects of host modulatory agents: A critical review. J Int Clin Dent Res Organ 2021;13:93-100

How to cite this URL:
Nirola A, Batra P, Bali BK. Comprehensive evaluation of adverse effects of host modulatory agents: A critical review. J Int Clin Dent Res Organ [serial online] 2021 [cited 2022 Aug 7];13:93-100. Available from: https://www.jicdro.org/text.asp?2021/13/2/93/335874

   Introduction Top

Inflammation is the physiological response to a variety of injuries or insults, including heat, chemical agents, or microbial infection. It is a highly orchestrated series of events that affects susceptible organs, tissues, and systems, including the periodontium. Under healthy or “normal” conditions, the inflammatory process enters a programmed resolution cycle activating natural pathways of healing. As in many other diseases in which inflammation is the central cause of pathology, periodontal diseases are characterized by the dysregulation or dysfunction of resolution pathways. The result is failure to heal and a chronic, progressive and destructive, nonresolving inflammation. It is critical to elucidate the common pathways of inflammation at activation and resolution stages and to identify both the cellular and molecular mechanisms involved.[1]

Inflammation includes both pro-inflammatory and pro-resolving mechanisms inherent to the body, in which the host attempts to confine and/or eliminate the invaders and when this is accomplished, actively resolves the pro-inflammatory response to limit self-damage. Hence, the body can actively control inflammation. Pro-resolving mediators are readily generated in tissues and limit leukocyte trafficking directed into the inflamed site, reverse the cardinal signs of inflammation, and coordinate the clearance of exhausted leukocytes, exudates, and fibrin, eventually leading to the restoration of function.[2] All of these inflammation-resolving processes limit and prevent tissue injury and further progression of acute inflammation into chronic inflammation. If the host fails to eliminate the injury, acute inflammation proceeds into a chronic phase and results in varying degrees of tissue injury.

Inflammation comprises a series of events that lead to a host response against trauma and microbial invasion, resulting in the liquefaction of surrounding tissues to prevent microbial metastasis and eventually in the healing of injured tissue compartments.[3] Periodontal diseases are inflammatory processes in which microbial etiological factors induce a series of host responses that mediate an inflammatory cascade of events in an attempt to protect and heal the periodontal tissues.

Host response modulation/host modulation is a term that has been introduced to the dental profession relatively recently. In the periodontal context, it means modifying or modulating destructive or damaging aspects of the inflammatory host response that develops in the periodontal tissues as a result of the chronic challenge presented by the subgingival bacterial plaque. Over the last two decades, a variety of pharmacological agents have been studied for a possible role as host modulators in the management of periodontal disease. These include nonsteroidal anti-inflammatory drugs, bisphosphonates, and the tetracycline family of compounds (and their chemically modified analogs). Newer agents that have the potential to be of benefit in periodontal treatment include anticytokine drugs (which have successfully been used in the treatment of rheumatoid arthritis), soluble cytokine blockers, and lipoxins. To date, only one systemic medication has been licensed specifically as a host response modulator for the treatment of periodontal disease, and that is subantimicrobial-dose doxycycline (SDD).

Although chronic inflammation progresses silently, it is the cause of most chronic diseases and presents a major threat to the health and longevity of individuals. Inflammation is considered a major contributor to several diseases. Inflammatory diseases share a common diagnostic and prognostic definition if they remain active: aberrant and uncontrolled inflammation of the target tissues and incurable progressive outcomes. The severity of the inflammatory pathological condition for the human's life depends on the affected tissues or organ system. In vital tissues such as the heart, lung, kidney, or liver, the progression of inflammation can be devastating. In peripheral tissues, however, the inflammatory process can follow a slowly progressive path. Thus, while the mediators may be similar, there exists a tissue specificity for the inflammatory events. Another major issue in understanding inflammation as an entity is the communication between distant organs. While it is plausible that inflammatory processes in one organ could directly lead to the pathologies in another organ or tissue, communication between distant parts of the body and their inflammatory states is mediated by common signaling mechanisms via cells or soluble mediators.[2]

The purpose of host modulation therapy is to restore the balance of pro-inflammatory or destructive mediators and anti-inflammatory or protective mediators to that seen in healthy individuals.

In the past, elimination of the microbial etiology was the focus and main tenet of periodontal therapy. Currently, however, many therapeutic approaches are focusing on how the host response can be manipulated in favor of controlling excessive inflammatory responses locally. Many aspects of the host response can be affected, including modification of proteolytic enzymes such as matrix metalloproteinases (MMPs), stimulation of cellular activity, and alteration of the extracellular matrix.

Modulation of these factors can cause gastrointestinal (GI) problems, hemorrhage (decreased platelet aggregation), renal and hepatic impairment, and bone loss accelerates when nonsteroidal anti-inflammatory drugs (NSAIDs) are stopped abruptly (rebound effect), inhibit bone calcification, induce changes in white blood cell count, and avascular necrosis of the jaws.[4]

Various host modulating agents to date have been employed and their favorable and adverse effects of these host modulatory agents will be discussed in this review article.

   Discussion Top

Host modulation therapy includes systemically or locally delivered pharmaceuticals that are prescribed as adjuncts to other forms of periodontal treatment. In periodontitis, the host is responsible for most of the tissue breakdown that occurs, leading to the clinical signs of disease. Host response modulators offer the potential for modulating or reducing this destruction by ameliorating excessive or pathologically elevated inflammatory processes to enhance opportunities for wound healing and periodontal stability. A variety of drug classes have been evaluated as host response modulators, including nonsteroidal anti-inflammatory drugs, bisphosphonates, and tetracyclines.

In periodontics, the concept of host modulation therapy is to reduce tissue destruction and stabilize or even regenerate the periodontium by modifying or downregulating destructive aspects of host response and upregulating protective or regenerative responses.[5]

Classification of host modulatory agents

The host modulatory agents can be broadly classified as

  • Agents preventing destruction (those which downregulate the destructive aspects of host response)
  • Agents promoting resolution and healing (those which upregulate the protective or regenerative responses).[6]

Nonsteroidal anti-inflammatory drugs inhibit the formation of prostaglandins, including prostaglandin E2, which is produced by a variety of resident and infiltrating cell types in the periodontium (including neutrophils, macrophages, fibroblasts, and epithelial cells) in response to lipopolysaccharide. Nonsteroidal anti-inflammatory drugs inhibit the formation of prostaglandins by blocking the cyclo-oxygenase pathway of arachidonic acid metabolism.

According to El-Shinnawi and El-Tantawy,[7] bisphosphonates are bone-seeking agents that inhibit bone resorption by disrupting osteoclast activity. They interfere with osteoblast metabolism and the secretion of lysosomal enzymes. More recent evidence has suggested that bisphosphonates also possess anti-collagenase properties. In 1985, Golub et al.[8] reported that tetracyclines have anti-collagenolytic activity and were proposed as a host-modulating agent for periodontal treatment.

According to Birkedal-Hansen et al.,[9] in addition to antibiotic properties, doxycycline can downregulate MMPs, a family of zinc-dependent enzymes that are capable of degrading extracellular matrix molecules, including collagen. MMPs are secreted by fibroblasts, keratinocytes, macrophages, polymorphonuclear neutrophils, and endothelial cells. Excessive amounts of MMPs are produced in inflamed periodontal tissue. These MMPs cause a breakdown of the connective tissue. Doxycycline downregulates MMPs.

According to Assuma et al.,[10] anticytokine therapy for periodontal diseases primarily targets production or actions of interleukin (IL)-1 β, IL-6, and tumor necrosis factor (TNF)-α because they are necessary for the initiation and progression of periodontal diseases and persistent production at the inflammatory site. By targeting the specific pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α via soluble antagonists, we can be able to arrest the periodontal disease progression.

Nonsteroidal anti-inflammatory drugs

They are used to treat pain, acute inflammation, and a variety of chronic inflammatory conditions. NSAIDs include the following:

• Salicylates (e.g., aspirin)

• Indomethacin

• Propionic acid derivatives (e.g., ibuprofen, flurbiprofen, naproxen).

   Adverse Effects Top

Velo and Rainsford (1992)[11] and Hawkey (1993),[12] reported that prolonged administration of NSAIDs is cautioned due to its adverse effects including GI upset, renal, gastroduodenal, hepatic, effectively treat periodontal diseases, and hemorrhage impairment due to nonselective inhibition of COX-1 and COX-2 enzymes.

Hawkey (1993)[12] in this paper reported that NSAIDs cause increased permeability in the stomach as they do in the rest of the GI tract. In the stomach, this is often described as breaking the mucosal barrier. The discovery of the ability of NSAIDs to inhibit prostaglandin synthesis led to the identification of many prostaglandin-dependent mechanisms underpinning the protection of the mucosa. These defense mechanisms are not dependent on prostaglandin synthesis. Synthesis of NO, via the constitutive enzymes, and sublative activation of enteric neurons result in a similar profile of responses to those subserved by prostaglandins. Some responses such as bicarbonate secretion may be critically dependent on mucosal blood flow and nonspecifically responsive to influences on it.

Smith and Dawkins[13] reported that maintenance of the mucosal barrier is an energy-dependent process that relies on adequate mucosal perfusion and can be compromised by inhibition of prostaglandin synthesis. As a result, the concept has developed that there are two routes to mucosal injury (particularly for aspirin), topical toxicity and inhibition of prostaglandin synthesis, it can in practice be difficult to quantify the relative contribution of each or to state with certainty whether all NSAIDs possess prostaglandin-independent topical toxicity.

Day et al.[14] reported that the ability of NSAIDs to impair hemostasis by inhibiting platelet cyclooxygenase may play a role when patients present with bleeding ulcers, particularly after a short history or (given its particular effect on hemostasis) when aspirin is used.

Stack et al.[15] and Weil et al.[16] conducted studies that have suggested an approximately 4-fold enhancement of the risk of ulcer bleeding, perforation, and death in elderly patients taking non-aspirin NSAIDs.

Van Dyke and Serhan[17] mentioned in their review paper that aspirin can trigger the biosynthesis of novel compounds, namely the adult T-cell leukemia, which can serve as potential endogenous anti-inflammatory signals or mediators of some of aspirin's newly recognized beneficial actions. These relatively recently recognized beneficial actions of ASA include prevention of myocardial infarction (Hennekens et al., 1994; Savage et al., 1995) and protection from colorectal adenoma, and other forms of cancer (Giovannucci et al., 1995; Levy, 1997). The mechanism of ASA's beneficial actions is likely to include the biosynthesis of 15-epi-LX and related compounds and could represent a novel mechanism for this “old drug” for which a wealth of toxicology data is available worldwide.

Aspirin has a blood thinner property which may lead to hemorrhage. This property poses as an adverse attribute when prescribing aspirin long term for the resolution of inflammation.

   Subantimicrobial Dose Doxycycline Top

All members of the tetracycline family downregulate MMP activity. This property was first identified in the early 1980s, during experiments in diabetes. Pioneering work in the 1980s with minocycline and other chemically modified tetracyclines led to the discovery that these compounds could inhibit MMPs and downregulate connective tissue destruction in inflammatory diseases independent of their antimicrobial activity.

More recent work has confirmed this therapeutic potential in studies of subantimicrobial-dose doxycycline (SDD) (20 mg) administered twice daily for 2 weeks to 18 months in the treatment of chronic adult periodontitis. Caton and Ryan.[18]

Several studies have evaluated the use of antibiotic therapy to stop or reduce the progression of periodontitis. Systemically administered antibiotics penetrate the periodontal tissues via the serum. Tetracyclines are effective in treating periodontal diseases in part because their concentration in the gingival crevice is 2–10 times that in serum.

It is the only MMP inhibitor that has been approved for clinical use in the US, Canada, and Europe and tested for the treatment of periodontitis. SDD. Periostat® is Food and Drug Administration (FDA) approved commercially available form. It is a 20 mg tablet formulation of doxycycline for oral administration. SDD, 20 mg twice daily for 2 weeks, significantly reduced collagenase activity in the GCF and gingival tissues of patients with adult periodontitis.

   Adverse Effects Top

These antimicrobial doses are often associated with the emergence of resistant bacteria esophageal and gastric ulceration.

Drug-induced esophageal ulcers were first reported in the 1970s by Yap et al.[19]

Carlborg et al.[20] stated that doxycycline is believed to act through a direct caustic effect on the esophageal and gastric mucosa, likely due to its acidic nature.

Sherman and Bini[21] reported that in animal studies, direct exposure of esophageal mucosa to tetracycline causes deep ulcerations.

Del Rosso et al.[22] stated that reported adverse effects of SDD included nasopharyngitis, diarrhea, headache, upper respiratory infections, hypertension, sinusitis, AST elevation, abdominal pain, fungal infection, and influenza.

Sloan and Scheinfeld[23] stated that GI side effects were present but tolerable. Marked blood pressure elevation was reported but not thought to be related to the study drug.

With a high safety profile and some mild adverse effects, the benefits of prescribing the SDD outweigh the risks.

   Bisphosphonates Top

El-Shinnawi and El-Tantawy[7] stated that bisphosphonates are chemically stable derivatives of inorganic pyrophosphate. Due to their affinity for the major constituent of bone (hydroxyapatite), they are incorporated into sites of active osteoclast-mediated bone resorption on the bone surface, allowing them to achieve a high concentration at local sites that affect osteoclast activity. More recent evidence has suggested that bisphosphonates also possess anti-collagenase properties. In human studies, these agents resulted in enhanced alveolar bone status and density.

   Adverse Effects Top

Upper GI adverse effects are the most commonly cited reasons for patient intolerance to oral bisphosphonates.

Greenspan et al.[24] reported nausea, dyspepsia, abdominal pain, and gastritis as the most common adverse effects due to alendronate.

The FDA recently issued an alert highlighting the possibility of severe and sometimes incapacitating bone, joint, and/or musculoskeletal pain that may occur at any point after patients begin taking a bisphosphonate.

Dicuonzo et al.[25] stated that transient hypocalcemia with secondary hyperparathyroidism is a recognized consequence of bisphosphonate administration. Due to the limited absorptive potential of oral bisphosphonates, hypocalcemia occurs most frequently after IV infusion and appears to occur most often in patients with hypoparathyroidism, impaired renal function, hypovitaminosis D, limited calcium intake, or high rates of osteoclast-mediated bone resorption (such as Paget disease of bone or a large skeletal tumor burden).

Wysowski et al.,[26] an epidemiologist, at the FDA described in a recent report that the use of oral bisphosphonates also appears to be associated with an increased risk of esophageal cancer.

From its approval of alendronate in 1995 through mid-2008, the FDA received reports of 23 patients taking alendronate who were diagnosed as having esophageal cancer, with a median time from use to a diagnosis of 2.1 years.

Woo et al.[27] reported that no potential adverse effect of bisphosphonate therapy has been more widely reported in the popular and clinical literature than osteonecrosis of jaws. Prolonged exposure to high doses of IV bisphosphonates appears to increase the risk of ONJ development.

In 2005, Odvina et al.[28] reported on nine patients who sustained atypical fractures, including some with delayed healing, while receiving alendronate therapy. Long-term bisphosphonate therapy might lead to over suppression of bone remodeling, an impaired ability to repair skeletal microfractures, and increased skeletal fragility.

Vitamin D (cholecalciferol)

Vitamin D is a fat-soluble circulating hormone. Safe sunlight exposure, along with diet and Vitamin D supplements, is the main source of Vitamin D.

Vitamin D is added to many fortified foods, including in dairy and whole-grain products. The endocrine functions of Vitamin D are mainly involved in the regulation of mineral ion metabolism by influencing calcium and phosphate homeostasis and thereby can influence the mineralization of bone and teeth.

Individuals consuming high doses of Vitamin D2 supplements could be at risk of Vitamin D intoxication, as some of the commonly used assays are unable to detect 25(OH) D2 and thereby might continue to show insufficient and/or false circulating 25(OH) D status based on the amount of 25(OH) D3. Individuals who are given Vitamin D as immunomodulatory agents are at risk of such intoxication. The innate immune system can be inhibited by Vitamin D. Here, Vitamin D has been shown to inhibit the differentiation, maturation, and immune-stimulating ability of dendritic cells by downregulating the expression of major histocompatibility complex class II molecules.

Garcia et al.[29] reported that calcium and Vitamin D supplementation may reduce the severity of periodontal disease if used at doses higher than 800–1000 IU daily and supported the rationale for testing the potential beneficial role of Vitamin D on periodontal disease in randomized clinical trials. They also noted that Vitamin D, in addition to its role in bone and calcium homeostasis, acts as an anti-inflammatory agent because it inhibits immune cell cytokine expression and causes monocyte/macrophages to secrete molecules that have a strong antibiotic effect.

   Adverse Effects Top

Although the mean lethal dose (LD50) of Vitamin D in humans has been estimated as 21 mg/kg (840,000 IU/kg), in reality, extremely high doses of supplement consumption would rarely raise the Vitamin D level that is deemed toxic and is used as evidence by the advocates of Vitamin D supplementation to convince the consumers of taking higher doses to supplement for prolonged periods.

The features of Vitamin D intoxication, including hypercalcemia and/or hypercalciuria, therefore, may persist for months despite the removal of the exogenous source of Vitamin D due to its lipophilic properties and storage in fat tissues.[30]

Enhanced bone resorption, as demonstrated by increased fasting urinary calcium excretion, is noted in the patients with Vitamin D intoxication; of importance, even after clinically normalizing the plasma calcium levels, the abnormally elevated fasting urinary calcium excretion and high serum 25(OH) D concentrations persisted.

Ozkan et al.[31] reported that in 27 reported cases of Vitamin D intoxication, the average serum calcium level was 12.1 ± 2.8 mg/dL and serum phosphate level was 6.1 ± 1.2 mg/dL; both serum calcium and phosphate levels were significantly higher than the accepted normal ranges. Of particular clinical importance, the mineral ion dysregulation induced by Vitamin D supplement consumption could exert harmful effects, even when serum Vitamin D levels show hypovitaminosis D state.

Rajah et al.[32] stated that a single dose (600,000 IU) of intramuscular injection of Vitamin D2 resulted in increased serum levels of phosphate beyond the normal range by 4 weeks and persisted till the follow-up period of 8 weeks, even when serum 25(OH) D level was below the normal range.

Brown and Razzaque[33] reviewed that prolonged and excessive consumption of Vitamin D supplementation can cause hypercalcemia and/or hyperphosphatemia leading to ectopic soft tissue mineralization.

Smith et al.[34] conducted a trial where 300,000 IU ergocalciferol given intramuscularly for 3 years to elderly people during fall season resulted in an increased risk of bone fractures.

   Omega 3-Fatty Acid Top

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are required for normal human development and metabolic function. The three most commonly ingested n-3 PUFAs are α-linolenic acid (18:3 ω-3, ALA), docosahexaenoic acid (20:5 ω-3, DHA), and eicosapentaenoic acid (22:6 ω-3, EPA). The primary source of ALA is certain seeds and nuts, whereas most dietary EPA and DHA come from seafood.

Fish oil supplementation at very high levels (equivalent of 5.4 g EPA and 3.2 g DHA) has been demonstrated to decrease superoxide and hydrogen peroxide generation in human neutrophils independent of the COX pathway or the release of lysosomal enzymes.

However, other studies indicate that changes in neutrophil and monocyte fatty acid composition resulting from low-to-moderate amounts of dietary LCn3PUFAs may not be accompanied by changes in ROS production or other cell functions chemotaxis and phagocytosis.

   Adverse Effects Top

Kromann and Green[35] have documented a reduced incidence of ischemic heart disease in populations with a high intake of n-3 fatty acids, there is also an unexplained increased incidence of stroke.

Dehmer et al.[36] apart from a high incidence of unpleasant side effects in patients taking fish oil supplements, clinical and laboratory studies have shown evidence of raised blood pressure in groups taking omega-3 fatty acid supplementation.

McClaskey and Michalets[37] reported the potential for undesirable anticoagulant effects with the concurrent use of fish oil and anticoagulant or antiplatelet medications that have previously been highlighted. They stated that older adults, in particular, may have an increased risk of major bleeding due to increased sensitivity to anticoagulation, multiple comorbidities, and polypharmacy.

Aspirin impinges the endogenous lipoxin-generating system during cell-cell interactions. Inhibition of prostaglandin biosynthesis by aspirin is a well-appreciated mechanism in its antithrombotic and anti-inflammatory effect.

El-Sharkawy et al.[38] studied the adjunctive treatment of chronic periodontitis with daily dietary supplementation with omega-3 fatty acids and low-dose aspirin. They concluded that dietary supplementation with ω-3 PUFAs and 81 mg aspirin may provide a sustainable, low-cost intervention to augment periodontal therapy.

   Anticytokine Therapy Top

Cytokines are small secreted proteins released by cells that have a specific effect on cell interactions and communications. Cytokine is a general name; other names include lymphokine (cytokines made by lymphocytes), monokine (cytokines made by monocytes), chemokine (cytokines with chemotactic activities), and IL (cytokines made by one leukocyte and acting on other leukocytes).

Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). There are both pro-inflammatory cytokines and anti-inflammatory cytokines. There is significant evidence showing that certain cytokines/chemokines are involved in the initiation and also persistence of pathologic pain by directly activating nociceptive sensory neurons.[39]

Periodontal destruction is initiated by bacteria that stimulate host responses leading to excess production of cytokines. Anticytokine therapy for periodontal diseases especially targets pro-inflammatory cytokines, that is, TNF-α, IL-1, and IL-6, because these are essential for the initiation of the inflammatory immune reaction and are produced for prolonged periods in periodontitis.[10],[11],[12] This therapy aims to bind the cytokines with the receptors present on target cells such as the fibroblasts. The three basic treatment strategies are.

  1. Neutralization of cytokines
  2. Blockage of cytokine receptors
  3. Activation of anti-inflammatory pathways, such as immune-suppressive pathways.

This new therapy can act as a host response modulator in the control of inflammatory diseases of gums and may provide the basis for new molecular therapeutic approaches to the treatment of periodontitis.

This therapy aims to bind the cytokines with the receptors present on target cells such as the fibroblasts.

   Anticytokine Agents Top

• Infliximab – Infliximab is a chimeric IgG monoclonal antibody. The term chimeric refers to the use of both mouse (murine) and human components of the drug

• Etanercept – Etanercept is a fusion protein. It links the human soluble TNF receptor to the Fc component of human IgG1.

• Anakinra – It is an IL-1 receptor antagonist. It competitively inhibits the binding of IL-1 to the IL-1 type receptor. Anakinra blocks the biological activity of naturally occurring IL-1, including inflammation and cartilage degradation

• Tocilizumab – It is a recombinant humanized anti-IL-6 receptor mAb that prevents the interaction of either the membrane-expressed receptor or its soluble counterpart with IL-6 and thus inhibits IL-6 signal transduction.

   Adverse Effects Top

Pichler and Campi B[40] concluded that biological agents are often highly potent tools in the treatment of various severe diseases. They can cause a variety of adverse side effects that often appear puzzling in the present state of research but may be very instructive as well. Biological-induced side effects should be differentiated from xenobiotic-induced side effects due to distinct chemical and biological features.

Maini and Taylor[41] stated that in trials with multiple administrations lasting 3–6 months, anti-TNF agents were associated with upper respiratory infections. However, it remains to be established whether long-term treatment increases the frequency of infections, particularly with organisms such as mycobacteria and listeria. They also reported the incidence of anaphylaxis and anaphylactoid reactions.

Nishimoto et al.[42] conducted a long-term study on the safety and efficacy of tocilizumab. They concluded that long-term use of tocilizumab leads to severe neutropenia.

According to Kanwar et al.,[43] the usage of IL-6 inhibitors in patients should be considered a risk factor for the development of invasive fungal infections like mucormycosis.

Recent use of anticytokine therapy in the management of COVID-19 has opened avenues in further understanding the safety and efficacy of this therapy.

The elevations of IL-6 and IL-10 are highly consistent in COVID-19. IL-6 targets the IL-6 receptor, and the letter recruits JAK, which transit cascade signal to activate signal transducer and activator of transcription 3.[44] IL-6 elevation is an overlapping parameter in both COVID-19 and Periodontal disease.

Targeting these cytokines by anticytokine therapy can control the inflammatory signs of periodontal diseases, open newer horizons on molecular level targeted therapies in the treatment of periodontitis, and act as an additional host modulating therapeutic approaches in controlling periodontitis. Further, studies are anticipated toward the use of anticytokine therapy shortly for better understanding and targeting the cellular and molecular pathways of periodontal disease pathogenesis.

   Conclusion Top

This review has sought to provide mechanistic overviews and clinical applications on the use of host modulatory therapeutic regimens for periodontal disease management and the demerits that may follow the use of these agents. The host modulatory agents discussed in this review apart from subantimicrobial doxycycline have not been approved by the FDA as their long-term use is under question. Drugs discussed in the review are prescribed to patients for various other conditions, but the use of these drugs for modulating the host response is still under scrutiny. NSAIDs, bisphosphonates, Vitamin D, and omega 3-fatty acid, anticytokine drugs have shown adverse effects when used for a long duration. Subantimicrobial doxycycline has shown a high safety profile with certain mild adverse effects. The benefits of prescribing outweigh the adverse effects of this drug. The key limitation is a gap of knowledge between the short-term evidence and the long-term use of these drugs. Although the average follow-up in randomized controlled trials is limited, these medications are often administered open-endedly over many years. Further research is required to assess the safe long-term use of these host modulatory agents in the treatment of periodontitis. A second gap between evidence and real-world practice is that the recommended long-term use of these drugs is based implicitly on a constant relative hazard assumption, meaning that the benefits continue (and stay constant) over the long-term when no data exist to confirm or refute this presumption. It is important to consider how the absolute risk changes over time.

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Conflicts of interest

There are no conflicts of interest.

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