Host-Modulation Therapy for Peri-Implantitis: Current Systemic and Future Medical Applications Recognizing the Potential Systemic Impact of Peri-Implantitis on Systemic Disease

Introduction

It is well known that current strategies for managing peri-implant mucositis and peri-implantitis are highly varied, and in many cases, unpredictable. This is an important issue since evidence suggests that the prevalence of peri-implant mucositis and peri-implantitis range from 22–43 percent of implants placed.¹ In most cases, the existing model for treating chronic periodontitis has been used for managing these implant-associated conditions, and with the possible exception of peri-implant mucositis, this approach has not been effective. In this regard, locally-applied antiseptics and antimicrobials after local debridement of the affected areas, have been used but with little success.² In some cases, regenerative treatments have also been used, following initial antimicrobial therapy (systemic and/or local) in order to re-create bone and other tissues lost as a consequence of peri-implantitis. Many reports suggest that some of the above-described treatments are useful, but predictability of outcome is poor and, in general, most investigations and systematic reviews/meta-analyses have shown that treatment for peri-implantitis, particularly antimicrobial treatment with debridement, is largely ineffective.³ Though there appears to be clinical similarity between the tissue destruction seen in patients with periodontitis and those with peri-implantitis, the underlying mechanisms of these conditions are probably quite different, with the possible exception of similarities between peri-implant mucositis and gingivitis. Therefore, in this report, we focus on issues pertaining to peri-implantitis, specifically its prevention as well as potential approaches for treatment.

We know that there are significant differences between the microbiomes associated with peri-implantitis and periodontitis, and this alone might explain why antimicrobial therapies developed for periodontitis do not apply to peri-implantitis.^4,5 Perhaps in this regard, we need to search for more appropriate antimicrobials based on differences in the microbiome. This said, the abject failure to treat peri-implantitis successfully, even with high concentration locally delivered antibiotics, suggests that anti-infective therapy might be considered as an adjunct to care but is unlikely to hold the ‘answer’ to treatment of these conditions. Notably, it has also been demonstrated that the level of inflammation about an affected implant, compared to a similarly affected tooth with periodontitis, is many times more severe.⁶ There is also evidence that salivary-rinse samples taken from patients with healthy-appearing implants demonstrate about a ten-fold higher level of polymorphonuclear neutrophil cells than saliva samples from mouths with healthy teeth.⁷ As yet, it is not known why there is such an amplification of inflammation around implants compared to similarly inflamed tissues around teeth, but this means that alternative treatment beyond antimicrobial strategies must be considered. In this regard, there is evidence suggesting that initial microbial infection could lead to surface release of titanium ions, and/or particles, which might create a chronic foreign body or inflammatory reaction that would then not be expected to respond to antimicrobial therapy.^8,9 In light of this background, we now describe alternate concepts that could be applied for management of peri-implantitis. In addition, we present an interventional approach that is designed to reduce the incidence of peri-implant mucosal inflammation as well as peri-implantitis.

We also suggest that peri-implantitis is even more of a concern to those patients with medical conditions including but not limited to diabetes, cardiovascular disease and dementia. Given that both the local and systemic inflammatory/collagenolytic responses in these patients is so elevated (as compared to natural teeth) and since there are clear correlations between oral inflammatory disease such as periodontitis and several non-oral/systemic conditions; peri-implantitis could represent an equal or possibly even greater risk insofar as systemic health impacts are concerned.^10,11 Hence we suggest that effective prevention and/or treatment of peri-implant diseases is of paramount importance not only for oral health but for systemic well-being as well.

2. Proposed Treatment Model for Prevention and/or Management of Peri-implantitis
We now propose that a relatively recent (although long-studied) clinical strategy called “host-modulation therapy” or HMT can provide advantages to counteract the above concerns regarding peri-implant disease including the probability that there will also be concomitant benefits to systemic health which were referred to above and are discussed below in some more detail. Clinically available (i.e., U.S. Food & Drug Administration-approved, as well as approval by government agencies in Canada & Europe), HMTs are based on NON-antibiotic formulations of doxycycline or more specifically subantimicrobial dose doxycycline (SDD). These are available by prescription either as 20 mg b.i.d., or 40 mg sustained-release formulations, administered orally, and produce blood levels too low (i.e., 0.4-0.6 ug/ml) to function as an antibiotic. Therefore, they can be prescribed to patients suffering from peri-implantitis safely for long periods of time.^12-14 As examples, Payne and Golub, in a NIH-funded double-blinded placebo-controlled study involving 128 post-menopausal women, demonstrated that a 2-year regimen of SDD not only significantly reduced periodontal disease severity (based on clinical, radiographic, and biochemical measurements) but also reduced diagnostic markers of systemic inflammation (e.g., hs-CRP and MMP-9) in their blood samples.^15-17 Also, in an earlier placebo-controlled study on patients with acute coronary syndromes (characterized by 1, 2, or 3 vessel atherosclerosis, unstable angina, and a history of myocardial infarction), a 6-month regimen of SDD again reduced systemic inflammation.^18,19

3. Periodontitis and Peri-implantitis
Although clinical and radiographic signs, as well as some symptoms of periodontitis and peri-implantitis, have many similar features, significant histopathologic and variations in clinical presentation still exist (for example, personal observations made by authors; pain seems more prevalent in patients with peri-implantitis). These variations may explain differences in disease onset and progression, and inevitably, the treatment modalities used to treat them. In comparison, peri-implant lesions generally form a more substantial defect of bone loss compared to periodontitis lesions. It is essential to understand the defect characteristics between periodontitis and peri-implant lesions, as this may shed light on the differences between these disease processes. For example, a study by Carcuac and Berglundh reported that experimentally induced peri-implantitis lesions were larger and extended closer to the bone crest than periodontitis lesions.²⁰ Additionally, periodontitis lesions, in contrast to peri-implantitis lesions, are usually confined to the alveolar bone by a zone of non-infiltrated connective tissue. These structural disparities appear to reflect and comport with our suggestion that there are fundamental biopathological differences between these two conditions and might be consistent with the notion that lesions observed in peri-implantitis seem to be much more inflamed than their dental counterparts. The absence of an epithelial lining between the lesion and the biofilm in the pocket (peri-implant pocket) may explain the abundance of neutrophil granulocytes in peri-implantitis lesions as significantly different to lesions in periodontitis.20 Furthermore, PMN-type MMP-8 has been shown to be elevated substantially in peri-implantitis lesions when compared to periodontitis lesions.^21,22 These differences indicate that the inflammatory response in peri-implantitis sites are more intense in promoting/recruiting both innate and adaptive inflammatory cells and therefore may produce greater inflammatory mediated disease. It is also noteworthy to consider that periodontitis and most certainly peri-implantitis are inflammatory diseases related to severely increased levels of oxidative stress. Therefore, it would seem important to also focus on approaches for the management of oxidative stress (in fact doxycycline has antioxidant activities on its own).

Regardless of the apparent differences discussed above regarding periodontitis and peri-implantitis it must also be recognized that both are at least induced by pathogenic bacteria leading to the initial presentations of oral inflammatory disorders involving the destruction of surrounding hard and soft tissues, mainly made up of type I collagen. The enzyme primarily responsible for the periodontal and peri-implant hard and soft tissue degradation is matrix metalloproteinase-8 (MMP-8), also known as neutrophil collagenase. These collagenases are adept at degrading almost all extracellular matrix and basement membrane protein components in physiologic repair and pathologic destruction of tissues. MMPs are produced by numerous cell types, including fibroblasts, endothelial cells, osteoblasts, macrophages, lymphocytes, and neutrophils, and are capable of degrading different components of the extracellular matrix (ECM) as well as factors that regulate cell motility. Due to these characteristics, the MMPs are of course also involved in numerous physiological processes, including angiogenesis, bone remodelling, wound repair, inflammation, and the immune response.

Furthermore, due to the almost ubiquitous role in tissue remodelling, MMPs are an essential indicator of tissue decomposition and is present in periodontitis lesions in both gingival and sulcular fluid. A study by Kiili et al. showed concentration of MMP-8 in the sulcular fluid of patients with chronic and aggressive periodontitis to be significantly higher than that found in healthy patients.²³ Further research by Xu et al. compared collagenase activity and MMP levels in gingival crevicular fluid and peri-implant sulcular fluid in patients with gingivitis, periodontitis, and peri-implantitis. The authors found that peri-implant sulcular fluid in patients with peri-implantitis contained the highest MMP-8 levels and activity. Indeed, there is evidence that the degree of MMP production in peri-implantitis lesions might be about 10-fold higher than that seen about teeth.6 It has also been demonstrated that MMP-8 levels of salivary and oral fluids are higher in subjects with localized and generalized periodontitis than in healthy controls, but these levels are reduced following nonsurgical periodontal therapy. To reiterate, as with periodontitis, MMP-8 levels were repeatedly found to be pathologically elevated in diseased peri-implant sulcular fluid. Xu et al. demonstrated a higher level of MMP-8 in peri-implantitis sulcular fluid than that detected in gingival crevicular fluid from periodontitis patients.⁶ Perhaps more importantly, periodontitis and peri-implantitis inflammatory markers where not only shown to be elevated locally but also demonstrated to have related systemic low-grade inflammation. Sorsa et al., in studying periodontitis, peri-implantitis and cardiovascular disease, found that both the oral fluid and serum MMP-8 analysis proved to be a useful biomarker as an indicator of systemic health and potential inflammatory mediated pathology.^24,25

With the continual investigation of the inflammatory response to periodontal disease, there is growing evidence that periodontal disease may play an essential part in the pathogenesis of certain systemic diseases. Studies have shown a possible link between chronic periodontal disease and systemic diseases such as atherosclerotic cardiovascular disease, diabetes, respiratory disease, kidney disease, rheumatoid arthritis, cognitive impairment, obesity, and cancer.²⁶ While there is good evidence for the link between periodontitis and various inflammatory systemic diseases, causality is still unclear. The link, however, could be related to the development of hyperactive neutrophil cells that begin to circulate in patients with periodontitis, gingivitis and probably peri-implantitis, although the effect of or relationships between the latter on systemic disease can at this point only be imputed.^27,28 It can be hypothesized that there might be at least two principal mechanisms that could explain, at least in part, the pathogenesis of links between systemic disease and periodontitis. We anticipate that these putative mechanisms could be relevant to the putative impact of peri-implantitis on systemic disease and will be outlined herein. The direct mechanism proposes that chronic periodontitis progresses through the ulceration of the epithelium lining of periodontal pockets, thereby providing direct entry of periodontal pathogenic bacteria (S. viridans, A. actinomycetemcomitans, P. gingivalis, M. micros) into the circulatory system.^29,30 The invasion of these pathogenic microbes to the circulatory system could then have access to various distant organs or systems thereby inducing disease/dysfunction therein. The indirect mechanism proposes that it is the inflammatory response to periodontal pathogenic bacteria that might explain the links between periodontitis and various systemic diseases. Chronic periodontitis as a source of chronic inflammation might set off a cascade of both innate and adaptive host responses that incite the pathogenesis of other inflammatory diseases in the body. To reiterate, peri-implant and periodontitis lesions are fundamentally different in their structure. As mentioned previously, peri-implant lesions lack an epithelial lining between the lesion and the biofilm. This distinguishing characteristic, among others, may explain the differences in the degrees of inflammation between peri-implantitis and periodontitis. Therefore, we propose that microbial or inflammation based models that purport to explain the links between oral inflammatory diseases such as periodontitis and peri-implantitis, might have to be distinguished from one another although even this is not clear.²⁰

With the mounting evidence suggesting the inflammatory host response to be greater in patients with peri-implantitis compared to periodontitis, the effective treatment of peri-implant diseases is of paramount importance not only for oral health but also for systemic wellness. Thus, there is a compelling rationale for future studies that define the potential impact of peri-implant disease on systemic inflammation. As noted above, current treatments that focus on antimicrobial therapy and various forms of debridement/decontamination of lesions found about implants with peri-implantitis have been, unfortunately, not reliable. Thus, alternate treatment approaches, particularly those focused on a broader array of treatments, including HMT and some extent control of the pathological biofilms, need to be explored.

4. Future Treatment Chemically-Modified Tetracyclines, Resveratrol and Topical Antimicrobial Coatings
Government-approved (Canada, USA, Europe) host-modulation through non-antimicrobial mechanisms of doxycycline inhibit matrix metalloproteinases thereby inhibiting the collagen and bone destructive enzymes associated with periodontitis. The matrix metalloproteinase inhibiting properties of low dose tetracyclines has developed into first generation host modulating therapeutics such as Periostat (and Aprillon for rosacea).³¹ The development and subsequent investigation of nonantibiotic formulations of doxycycline has demonstrated, through numerous clinical trials, that these are safe and effective adjuncts in the treatment of periodontitis. This has given rise to the development and study of new HMTs where a new strategy has emerged which involves the modification of the chemical structure of the tetracycline molecule. The objective was to eliminate the antibacterial activity of the drug but to retain or enhance its host-modulating properties (matrix metalloproteinase-inhibition). As a leading example of these chemically modified tetracyclines (CMTs), CMT-3 (or COL-3), have shown promise as effective second-generation medications for HMT. In vitro and animal studies have shown CMT-3 to be a potent matrix metalloproteinase inhibitor while being chemically modified to remove its antibiotic activity. Moreover, CMT-3 used in human clinical trials, has been shown to be safe, and to demonstrate significant anti-angiogenic activity in patients with cancer, Kaposi’s sarcoma (see below). This may allow for CMTs to have a greater effect on MMP inhibition in comparison to previous nonantibiotic formulations of doxycycline.³²

Along similar lines, there is ample evidence showing that resveratrol, being a potent antioxidant will not only prevent bone loss observed in experimental models of periodontitis but in a dimer form (gnetin-c) can even reverse bone loss in models of experimental periodontitis, as shown by Ikeda et al., even if the irritating/infectious triggers are left in place.³³ In addition, resveratrol is a known antagonist of the aryl hydrocarbon receptor, a receptor that when activated by cigarette smoke compounds, known as aryl hydrocarbons, inhibits bone formation.³⁴ Its use may become important when treatment must be done for smokers or those who quit smoking less than 10 years prior to implant/periodontal therapy. However, resveratrol has significant issues that need to be addressed before having therapeutic potential, including but not limited to, bioavailability.³³

Another example of a second-generation HMT, curcumin, an herbal derivative of turmeric, has been used for a variety of diseases such as ulcerative colitis, inflammatory bowel disease and cancer to name a few. Chemical modification of this compound has improved solubility, absorption rates and bioavailability. These modified curcumins, while inhibiting a different spectrum of inflammatory mediators, has shown effective reduction in alveolar bone loss in animal models of periodontal disease. Their effects have been attributed to inhibition of proinflammatory compounds including metalloproteinases as well as to its antioxidant properties (like resveratrol).^35,36,37

In relation to treatment of microbial infection, we have made the point that periodontal pathogenic bacteria play an important role in the initiation of peri-implantitis.

This of course has many etiologies some of which can be iatrogenic in origin. For example, improper three-dimensional position of the implant within the hard and soft tissue may allow for bacterial contamination of a roughened implant surface that is exposed to the oral environment. Suboptimal emergence profiles of the implant prosthetic can make cleansability of the implant/prosthetic surface virtually impossible. Addressing these compromises are often required prior to any decision on long term peri-implant disease management strategies. Bacterial contamination of the implant and its surrounding tissues remains a burden to maintaining peri-implant health and at times impossible to rectify.

However, it is reasonable to presume that even if eradication of these microbes cannot be relied upon to ‘cure’ peri-implantitis, that their removal will at least improve the clinical presentation of this condition. Moreover, and as referred to above, it is highly probable that microbes of various types must play an important role in the initiation of peri-implantitis. Therefore, another proposed treatment that could be included in this protocol (along with other methods of debridement) would involve the use of a topical antiseptic that in effect normalizes the oral biofilm, ridding it of periodontal pathogens as well as cariogenic pathogens (Prevora®). This can be applied simply and painlessly while it will provide profound reductions in pathogenic levels of oral microbes, thereby potentially preventing the development of peri-implant mucositis and peri-implantitis while also reducing bacterially mediated stimulation of local inflammation. Of course, if systemic dissemination of oral pathogens does play an important role in the effects of peri-implantitis or periodontitis on systemic disease, the use of this type of antiseptic as part of this treatment model would be sensible.

5. Additional Medical Benefits
As stated previously, there is an abundance of evidence indicating that collagenases, including MMPs, play an important role in periodontal tissue destruction as well as other tissues. Since collagen is the foremost structural protein in all connective tissues of the human body and because MMPs are instrumental in the degradation of the collagen matrix, it is not surprising that any new medication that can inhibit MMPs would be expected to have widespread medical and dental applications. One such example is the involvement of MMPs in tumor invasion and metastasis in cancer cells. Metastasis of all cancers is mediated significantly by MMPs that remodel the extracellular matrix. By removing physical barriers to invasion through ECM degradation, and modulation of cell adhesion and upregulation of biologic activity such as angiogenesis, MMPs play multiple vital functions in facilitating tumor cell metastasis. Therefore, the potent MMP inhibitory activity of tetracyclines may have a potential role in cancer treatment modalities. Studies by Cianfrocca et al. and Dezube et al., in their assessment of the plasma levels of MMPs and assessment of Kaposi Sarcoma (KS) lesion formation, revealed that CMT-3, when given orally produced a significant decrease in KS lesions and a significant decrease in MMP-2 and MMP-9 activity. The authors concluded that CMT-3 may be a promising drug for the treatment of neoplasms associated with AIDS through the inhibition of MMPs.^38,39

Matrix metalloproteinases have also been associated with acute lung injury after cardiopulmonary bypass surgery clinically. Carney et al. in a randomized animal (Yorkshire pigs) study found that CMT-3 prevented acute lung injury, typical after cardiopulmonary bypass, compared to sham bypass surgery.⁴⁰ Thus, MMPs are a collective of bioactive molecules and are capable of degrading a vast array of host extracellular matrix proteins not only in the mouth but also systemically. While periodontitis and peri-implantitis are inflammatory mediated diseases in the oral cavity it would be prudent to note the ubiquitous nature of inflammatory mediated diseases to the human body and recognize that the host’s inflammatory/collagenolytic response is the arbiter of tissue breakdown. Therefore, host modulation therapies are being incorporated into several other inflammatory mediated diseases involving the cardiovascular, pulmonary, dermatology, and rheumatology systems. When combined with resveratrol (systemic/topical) as well as tools for normalization of the oral biofilm, it can be anticipated that this form of treatment could be used preventively and of course during the course of management of peri-implantitis.

6. Peri-implant Mucositis and Peri-implantitis
With more than an estimated 5 million implants placed in the United States and growing, peri-implant diseases are becoming more of a concern to the dental clinician with very inconsistent and rudimentary treatments at this time. While dental implants are indeed recognized as an important treatment strategy by both the patient and the dental surgeon the negative impact of peri-implant disease is not as well defined compared to the well-established negative impact of periodontitis both locally and systemically. Considering the high incidence of peri-implant mucositis and peri-implantitis (22-43%), there is growing need to better understand these disease processes, its impact on the patient both locally and systemically as well as improve treatment therapies.¹ There is now a compelling and pressing rationale for future studies on the understanding of the pathophysiology as well as potential therapies for peri-implantitis and peri-implant mucositis. By doing so we hope to define both the local and systemic impact of peri-implant disease, define the inflammatory process of periimplant disease and assess the efficacy of host modulation therapies both locally and systemically as potential therapies for peri-implant disease.

In addition to clinical findings reported in the case series shown in Table 1, we have also tested oral inflammatory load (counts of oral PMN cells) in patients who were totally edentulous, had ‘healthy’ implants, or had implants with peri-implantitis. The findings shown in Figure 1, suggest that although the overall counts are lower than seen in patients who have generalized and severe periodontitis (the test patients had only 2-3 implants with inflammation for example, or 3-5 healthy implants), there are still some interesting observations. In edentulous patients, there were very few detectable PMNs (likely arising from salivary glands). However, even in the presence of healthy appearing implants, there is a 10-fold increase in oral PMN counts and yet another 10-fold increase in patients with diseased implants. These findings might suggest that even in the presence of healthy-appearing implants, the ingress of PMNs to the oral cavity increases and could suggest low level inflammation or parainflammation perhaps. In the presence of diseased implants though, there is an even greater ingress of oral PMNs suggesting that the degree of oral inflammation could be an important factor to consider insofar as the relationships between oral inflammatory diseases and systemic diseases might be concerned.

Table 1

Fig. 1A

Oral neutrophil (PMN) numbers in 5 edentulous patients. The Y axis ends at 2.5 indicating that the overall count is basically nil to extremely low. These PMNs probably arose from the salivary glands.

Fig. 2B

Oral PMN levels in 5 patients who had a total of 2-3 implants but were clinically not inflamed. Despite the absence of clinical evidence for inflammation, note that the Y axis now goes up to 9.0 suggesting either low grade inflammation, PMN leakage, or ‘para-inflammation’.

Fig. 1C

In this case oral PMN counts were obtained from 4 patients with 2 implants surrounded by inflamed tissues. In this case the Y axis ends at 250 suggesting a large increase in oral PMN levels in this patient group.

Summary
We propose that inflammatory disease about implants should have the same and possibly greater impact on the incidence and severity of systemic diseases that have already been associated with periodontitis. Long-term administration of Periostat® (3-17 years) might effectively prevent and treat peri-implantitis in combination with resveratrol and Prevora®.

Oral Health welcomes this original article.

Corresponding author: H. C. Tenenbaum, DDS, Dip Perio, PhD, FRCD(C). Dentist in Chief, Sinai Health System and Centre for Advanced Dental Research and Care, Professor of Periodontology, Faculty of Dentistry Professor of Laboratory Medicine and Pathobiology, Faculty of Medicine University of Toronto Canada. howard.tenenbaum@sinaihealth.ca

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About the Authors

Steve Chang, Faculty of Dentistry, University of Toronto, Canada; Michael Glogauer, Faculty of Dentistry, and Centre for Advanced Dental Research and Care, Department of Dentistry, Sinai Health System, University of Toronto, Canada; Lorne Golub,, Stony Brook University, New York, USA; Joseph Bacigalupo, Private Practice, Hempstead, New York; Timo Sorsa,, University of Helsinki, Finland; Philip M. Preshaw, Newcastle University, UK; Hsi-Ming Less, Stony Brook University, USA; Howard C. Tenenbaum, Faculty of Dentistry, and Centre for Advanced Dental Research and Care, Department of Dentistry, Sinai Health System, University of Toronto, Canada.

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