Peri-implantitis, systemic inflammation, and dyslipidemia: a cross-sectional biochemical study

Peri-implantitis is a common immune-mediated inflammatory condition of bacterial origin, which is characterized by peri-implant soft tissue inflammation and bone loss around implants [1]. Recent epidemiological studies reported a high prevalence of this disease worldwide, affecting between 24% and 45% of individuals with implants [2, 3, 4, 5]. When compared to periodontitis, peri-implant lesions might be considered as “more invasive,” as an increased immune response and osteoclastogenesis are present; furthermore, as a result of the lack of epithelial lining between the peri-implant lesion and the apical portion of the peri-implant pocket, infection can reach the alveolar bone [6].

Recent animal studies have shown elevation of peripheral levels of pro-inflammatory biomarkers (e.g., total protein, albumin, and white blood cells [WBC]) after ligature-induced experimental peri-implantitis [7, 8]. It is worth mentioning that the surgical treatment of experimental peri-implantitis by means of open flap debridement led to a reduction of these systemic inflammatory parameters, which reached similar values to baseline [7, 8]. It could be hypothesized that similarly to periodontitis, the inflamed and ulcerated peri-implant pocket epithelium allows the entrance of locally produced inflammatory mediators (e.g., leukocytes and cytokines) into the bloodstream, evoking a systemic immune and acute inflammatory response that subsequently could interact with lipid metabolism, thereby elevating blood levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which in turn may increase the risk of atherosclerotic disease. This is supported by previous experimental studies where long-term oral infection with lipopolysaccharide from Porphyromonas gingivalis in B6 Apoehl mice was associated with elevated very-low LDL, LDL, and total cholesterol levels, as well as reduced high-density lipoprotein levels due to an increase in liver-produced pro-inflammatory mediators, such as interleukin-6 (IL-6) [9]. There is also evidence that infection and inflammation may contribute to a pro-atherogenic lipid profile by overproduction of oxidized LDL [10]. Based on this, patients with peri-implantitis could present a similar systemic state to that seen in periodontitis patients. To our knowledge, there is a lack of clinical studies evaluating whether patients diagnosed with peri-implantitis have an exacerbated systemic pro-inflammatory state with dyslipidemia.

The aim of the present investigation was 2-fold: firstly, to investigate the relationship between peri-implantitis and systemic inflammation; and secondly, to analyze whether this systemic inflammatory state in peri-implantitis is associated with dyslipidemia.

A cross-sectional biochemical study was carried out following the STROBE guidelines [11]. The research was performed in accordance with the Declaration of Helsinki of the World Medical Association (2008) and was approved by the Ethics Committee of the Servizo Galego de Saúde and Xunta de Galicia (2016/399 and 2017/508). Written informed consent was obtained from each patient after a full explanation of the oral examination and blood sample collection.

The peri-implantitis patients and controls were similar in terms of age and sex (P=0.995 and P=0.917, respectively). Although a higher percentage of current smokers were detected in the case group than in the control group, this difference was not statistically significant (P=0.472). Nevertheless, more than 3-quarters of the cases (13 of 16) presented a previous history of periodontitis in comparison to none of controls (0/31) (P<0.001). As expected, the values of clinical peri-implant parameters such as PPD and BoP were significantly higher in peri-implantitis patients (both P<0.001) (Table 1). These results did not differ when linear mixed analysis was performed, accounting for the number of implants per patient (Table 1). The total number of implants was 20 and 36 in the case and control groups, respectively. The mean number of implants per patient was similar between groups (1.2±0.7 vs. 1.1±0.4, P=0.985).

Table 1
Study sample characteristics (n=47)

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Raw (unadjusted) data for lipid fractions, metabolic parameters, complete blood count, and inflammatory biomarkers are displayed in Table 2. Patients with peri-implantitis exhibited higher circulating levels of cholesterol (P<0.001), LDL cholesterol (P=0.001), WBC (P<0.001), monocytes (P<0.001), and TNF-α (P=0.033) than healthy controls. In contrast, serum levels of IL-10 were lower in subjects with peri-implantitis than in controls (P<0.001). These results did not differ when linear mixed analysis was performed, accounting for the number of implants per patient (Table 2). Only the neutrophil concentration showed a statistically significant difference between groups (P=0.034).

Table 2
Biochemical characteristics (n=47)

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After adjustment for a history of periodontitis, statistically significant differences between the peri-implantitis patients and controls remained for total cholesterol (estimated adjusted mean difference, 76.4 mg/dL; 95% confidence interval [CI], 39.6, 113.2 mg/dL; P<0.001), LDL cholesterol (estimated adjusted mean difference, 57.7 mg/dL; 95% CI, 23.8, 91.6; P<0.001), WBC (estimated adjusted mean difference, 2.8×10³/μL; 95% CI, 1.6, 4.0×10³/μL; P<0.001) and IL-10 (estimated adjusted mean difference, −10.4 pg/mL; 95% CI, −15.8, −5.0 pg/mL; P<0.001), but not for TNF-α (estimated adjusted mean difference, 7.6 pg/mL; 95% CI, −60.2, 75.5 pg/mL, P=0.821) and monocytes (estimated adjusted mean difference, 0.2×10³/μL; 95% CI, −0.2, 0.6×10³/μL; P=0.252).

While modest positive correlations were found between PPD and total cholesterol (r=0.512; P<0.001) (Figure 1A), LDL cholesterol (r=0.463; P=0.001) (Figure 1B) and WBC (r=0.519; P<0.001) (Figure 1D), a moderate negative correlation was found between IL-10 and PPD (r=0.609; P<0.001) (Figure 1C) in all participants. Similar, but slightly higher, estimates were observed for BoP and total cholesterol (r=0.602; P<0.001), LDL cholesterol (r=0.483; P=0.001), WBC (r=0.630; P<0.001), and IL-10 (r=−0.758; P<0.001).

Figure 1
Scatter plots showing correlations between PPD (mm) and: (A) total cholesterol (mg/dL); (B) LDL cholesterol (mg/dL); (C) IL-10 (pg/mL); (D) WBC (10³/μL).
PPD: probing pocket depth, LDL: low-density lipoprotein, IL-10: interleukin-10, WBC: white blood cells.

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To the best of our knowledge, this is the first study assessing the inflammatory profile of patients with peri-implantitis. The findings of this pilot study showed an enhanced systemic inflammatory state characterized by elevated levels of WBC as well as the presence of dyslipidemia in patients with peri-implantitis compared to individuals with healthy implants. We found moderate linear correlations of the depth of the peri-implant pockets and peri-implant bleeding with markers of inflammation (WBC and IL-10) and blood lipids (total cholesterol and LDL cholesterol).

In peri-implantitis, the presence of subgingival pathogens elicits a local inflammatory response, which is characterized by larger proportions of polymorphonuclear leukocytes and macrophages. Furthermore, this inflammatory response is amplified due to the production of pro-inflammatory cytokines and prostaglandins. The release of these substances into the bloodstream stimulates further recruitment of pro-inflammatory mediators and leukocytes at the local site. It should be highlighted that it has been demonstrated that this local inflammatory response is more pronounced in peri-implant tissues than in periodontal tissues [6]. The ulcerated gingival epithelium of severely periodontally affected patients allows these locally produced inflammatory mediators to enter the bloodstream and induce an acute-phase reaction in the liver, thereby contributing to the overall systemic inflammatory burden [13]. If we take into account the pathophysiological similarities of both diseases, a persistent peri-implant inflammatory state might also have an impact on systemic inflammation. In the present study, patients with peri-implantitis had an increase in leukocytes (WBC), reflecting a possible chronic systemic inflammatory stimulus, which might have been caused by the persistent peri-implant disease, as has been shown recently in periodontitis [14]. A linear correlation was also found between clinical peri-implant inflammatory parameters and WBC levels. Along similar lines, recent animal studies have shown an increased systemic inflammatory response after ligature-induced experimental peri-implantitis that was characterized by high levels of total protein, albumin, and WBC, which reverted to baseline after surgical peri-implant treatment [7, 8]. The systemic inflammatory state of peri-implantitis patients was confirmed by lower circulating levels of IL-10, a cytokine with important anti-inflammatory properties [15]. It has been suggested that decreased levels of IL-10 may favor a more inflammatory milieu since IL-10 has potent deactivating properties in macrophages and T-cells, and thus can act as a downregulator of cell-mediated immune responses, such as those potentially seen in peri-implantitis [15].

Another relevant finding from this study is that the peri-implantitis patients exhibited dyslipidemia, as characterized by higher blood LDL cholesterol levels. This observation confirms previous results reporting higher LDL cholesterol and total cholesterol levels among periodontitis patients when compared to healthy controls [16, 17, 18]. A relationship between infections and lipid metabolism has been widely documented in the past decades. Chronic infectious diseases are now thought to have an impact on lipid plasma levels [19, 20, 21]. This dyslipidemia is thought to be part of a host response aimed at decreasing the toxicity of harmful microbiological agents [22]. The present investigation found an association between peri-implantitis and abnormal lipid levels, which may be mediated by the constant activation of the inflammatory process determined by the presence of periodontal pathogens in peri-implant pockets.

Based on the present results, one might speculate that peri-implantitis could be associated with atherosclerotic disease. The acute-phase response during peri-implant infection/inflammation protects the host from further infection. Changes in acute-phase proteins (e.g., C-reactive protein [CRP]) neutralize invading microorganisms such as periodontal bacteria, minimize the extent of tissue damage, participate in the local immune response and tissue regeneration, and replenish proteins used in the inflammatory process [22, 23]. These changes, if present for a prolonged period of time, can lead to detrimental consequences to the host, such as the development of low-grade chronic systemic inflammation. In this sense, changes in acute-phase reactant synthesis are mediated by cytokines produced in response to a variety of stimuli in multiple cell types, including macrophages, monocytes, lymphocytes, and endothelial cells [24, 25]. Cytokines responsible for the coordination of both immune and inflammatory responses such as ILs or TNF-α might induce alterations in lipid and lipoprotein metabolism that contribute to atherogenesis [22]. Due to the high prevalence of peri-implantitis and atherosclerotic vascular diseases such as coronary heart disease and stroke, future epidemiological studies should investigate whether individuals with peri-implantitis are at a high risk of having cardiovascular events.

Some shortcomings need to be acknowledged in relation to our investigation. Firstly, this was a pilot study and, therefore, the results are preliminary and hypothesis-generating. However, post hoc power calculation was performed, showing that our study had a power of 90% to detect clinically meaningful differences between peri-implantitis patients and controls in terms of WBC concentrations. Secondly, due to the cross-sectional nature of the study, causality cannot be demonstrated; hence, we cannot rule out the possibility that other factors could also be involved in the upregulation of peripheral inflammatory mediators and dyslipidemia seen in peri-implantitis patients. Although all participants were in apparent good general health, some of them could have suffered from undiagnosed medical conditions such as pre-hypertension, pre-diabetes, or obesity. In this sense, a recent study demonstrated that an extremely high body mass index (≥40 kg/m²) was associated with worse peri-implant conditions, increased systemic pro-inflammatory state and dyslipidemia [26]. In the present investigation, an important factor that might have influenced the results was the previous history of periodontitis, as most of the peri-implant cases presented with successfully treated periodontal disease. Even after adjustment for this confounding factor, significance remained for levels of WBC, IL-10, cholesterol, and LDL. In addition, when the clinical peri-implant assessment was done and blood samples were collected, none of the patients had active signs of periodontitis, which therefore might not have had a strong impact at a systemic level. Another limitation is that commonly used serum biomarkers reflecting systemic pro-inflammatory processes such as CRP or IL-6 were not measured in this study. Nevertheless, WBC has been widely used in the literature as a surrogate marker of systemic inflammation [27]. We also included a well-known cytokine with anti-inflammatory action (IL-10) [15]. Our results showed not only that concentrations of WBC were elevated in peri-implantitis patients, but also that IL-10 serum levels were reduced when compared to subjects with healthy implants, thus supporting our initial hypothesis.

It can be concluded that otherwise healthy patients diagnosed with peri-implantitis presented with a low-grade inflammatory state (increased circulating levels of WBC) accompanied by dyslipidemia (increased blood levels of cholesterol and LDL). Further studies are warranted to confirm our preliminary results using large population-based cohorts. Experimental studies are also needed to investigate the potential biological mechanisms behind this link. Lastly, carrying out intervention studies will be of paramount interest to test whether non-surgical and surgical peri-implant therapy could have a beneficial systemic effect in terms of reducing the overall inflammatory burden in patients affected by peri-implantitis.