The Relationship of Peri-implantitis With COX-2 Gene Polymorphisms, Active MMP-8 Levels, and Characterization of Associated Microbiota.

Dental implants have become an integrated part of modern dentistry during the last decades. Since osseointegration (the process of an implant being incorporated into the jawbone) was discovered, implant dentistry has gone substantial steps over time. Dental implants comprise of an endosteal part made of titanium and an external prosthetic part, aiding in the rehabilitation of edentulous patients. They offer the possibility to patients missing one or several teeth to achieve the maximum functional and esthetic results, refraining from traditional dentures that are quite unpleasant. Implant industry is gradually growing. Overall, the global market of dental implants was valued at US$ 2,91 billion in 2016 with more than 8.809 million implants placed annually in the US (1). However, the prevalence of biological complications regarding dental implant supported restorations is growing in the same rate (1).

The term "Peri-implantitis" was introduced in the 1st European Workshop of Periodontology in 1994 and since then numerous definitions have been proposed to describe the bone loss that characterizes the aftermath of implant installation (2,3). Peri-implantitis and peri-implant mucositis are covered under the term peri-implant diseases and are considered analogous to periodontal diseases (4). Currently, peri-implantitis is defined as the pathological condition around dental implants characterized by inflammation in the peri-implant mucosa and progressive bone loss, eventually jeopardizing the fate of the implant (5). The number of studies referring to peri-implantitis have risen in the last 30 years according to PubMed, from 86 papers in the 90s' to a total of 1938 manuscripts until now (1). The prevalence of peri-implantitis is also exhibiting growing rates. In a systematic review, Zitzman and Berglundh in 2008 reported a prevalence ranging from 12 to 56% (3). More recent studies reveal a prevalence of 22% (1-47%) (6), 20% (7), 26% (8), and 28% (9). It should be pointed that in the previous studies the exact prevalence of the disease is difficult to estimate and is dependent on several factors including the diagnostic criteria of the disease and the time point chosen for the evaluation (10). However, it is obvious that peri-implantitis is a growing problem affecting implant dentistry and will certainly be the topic of many future studies.

Several protocols have been proposed for the treatment of peri-implantitis including, non-surgical protocols, with implant decontaminating devices and lasers and surgical protocols such as the use of regenerative materials (11,12) . However, if peri-implantitis is already established, the proposed strategies and recommendations for its treatment can still be considered as empirical. From the existing evidence it seems that nonsurgical therapy is not effective, at least not in advanced cases. Surgical techniques may be necessary to provide us with adequate access to degranulate the inflamed tissues effectively as well as to decontaminate the implant surface (13).

The Consensus report of Workgroup 4 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions concluded that peri-implantitis is an inflammatory process of a microbial origin that causes bone loss (4). In addition, several risk factors have been proposed as potential co-drivers in this entity, including history of periodontitis, smoking, diabetes and poor plaque control (5). Factors such as genetic predisposition and release of titanium particles have also been indicated as potential risk factors (14). The microbial involvement in peri-implantitis initiation and progression has been established, however recent studies suggest that peri-implantitis may be a result of a foreign body reaction, emphasizing the role of the host response in the disease initiation. (15). In other words, the aetiology of the disease is yet to be elucidated. However, using conventional DNA probe and cultural analyses, common periodontopathogenic bacteria have been isolated at both healthy and diseased implant sites (16) and the distribution of the detected species did not markedly differ by clinical implant status (17). However, when compared with healthy implant sites alone, peri-implantitis was associated with higher counts of bacterial species considered as consensus periodontal pathogens including Porphyromonas gingivalis and Tannerella forsythia (18). Moreover, observational studies have indicated that peri-implantitis was more frequently linked with opportunistic pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus ,(19,20) fungal organisms (e.g. Candida albicans, Candida boidinii, Penicillum spp., Rhadotorula laryngis, Paelicomyces spp.),(21,22) and viruses (i.e. human cytomegalovirus, Epstein-Barr virus), (23) thus pointing to a rather complex and heterogenous infection. Therefore, the recognition of the exact bacterial composition of peri-implant lesions is of paramount importance.

A significant observation about implant failures is that usually, a small number of patients lose many implants. This clusterization phenomenon has been identified in many studies (24,25). Weyant and his colleagues examined the survival rate of implants in 598 patients and noticed that more than half of the cases that received multiple implants had more than one failure. They estimated that patients who had one implant lost were 1.3 more likely to lose more implants (26). These findings led to the hypothesis that host factors affect implant survival and therefore genetic predisposition may play an important role in the development of peri-implantitis. Many gene polymorphisms have been evaluated. Initially, most of the studies referred to polymorphisms of cytokines which play a key role in the immune response (27-29), such as the interleukins IL-1α, IL-1β, and their antagonist protein IL-1ra, IL-6, IL-10, IL-17, TNF-α and Transforming Growth Factor-β1 (TGF-β1). Apart from these, various other genes have been investigated, e.g. genes encoding CD14, receptor activator of nuclear factor kappa B ligand (RANKL), microRNAs, bone morphogenetic proteins (BMPs), fibroblast growth factor (FGF), TRAF family member-associated NF-kappa-β activator (TANK), serine/threonine-protein kinase B-Raf (BRAF), calcitonin receptor (CTR), haptoglobin. There are many discrepancies in the results of the above-mentioned studies. Some succeeded to detect possible associations and others not. A more novel gene polymorphism mentioned in genetic studies is that of the cyclooxygenase-2 (COX-2). A single nucleotide polymorphism of COX-2 has been shown to alter the expression of the COX-2 gene. Several studies have found an association among COX-2 gene polymorphisms and periodontitis (30-32). However, in the case of peri-implantitis data is scarce.