Impact of Cigarette Smoking on Peri-implant Cytokine Profiles: A Systematic Review and Meta-analysis

Abstract

Studies have suggested that cigarette smoking may increase inflammation around dental implants by inducing higher levels of proinflammatory cytokines in diseased and healthy implants. The purpose of this article is to systematically compare peri-implant cytokine profiles around healthy and diseased implants in smokers versus non-smokers. Using appropriate MeSH and keywords, an online search was conducted for prospective clinical studies in which the peri-implant cytokines in healthy and diseased dental implants in smokers were compared with those in non-smokers. The data and outcomes were tabulated, and the quality of the literature was assessed. Meta-analysis was conducted on cytokines that had been evaluated in more than one study. Of the 1,592 items, 10 articles were included in this review. In heathy dental implants, cigarette smoking had a statistically insignificant effect on the cytokine profile. During peri-implantitis, smoking had a more significant effect on the levels of proinflammatory cytokines such as IL-1β and MMP-9, but there was significant heterogeneity between the studies and the sample size was not adequate to ascertain the overall long-term impact. Nine out of 10 studies in this review had several sources of bias and were of low quality, and one study had a moderate quality. Within the limits of this systematic review, it may be suggested that cigarette smoking aggravates peri-implantitis by influencing the cytokine profile to proinflammatory. The effect of cigarette smoking on clinically healthy implants is uncertain.

 

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Keywords

cytokines - periodontium - peri-implant health - periodontitis - smoking

Introduction

Peri-implantitis is an inflammatory disease of the hard and soft tissues that surround the dental implant.[1] If untreated, it leads to irreversible loss of the bone and subsequent loss of osteointegration and implant failure. It has been estimated that as many as 20% of patients who have received dental implants are affected by the disease.[2] Lack of adequate oral hygiene is the main risk factor that has been implicated in peri-implantitis.[3] Other risk factors include cigarette smoking, immunocompromising diseases, uncontrolled diabetes, unfavorable occlusal forces, and genetic polymorphisms.[3]

Cigarette smoking remains a classical risk factor for peri-implant disease and early implant failure.[4] Studies have suggested that cigarette smoking may increase inflammation in the peri-implant tissues by increasing the levels of proinflammatory cytokines in the peri-implant sulcular (or crevicular) fluid (PISF).[5] Other studies have observed comparable implant survival rates between non-smokers (NS) and smokers if the abutments are placed immediately on the day of surgery.[6] Recent literature also emphasizes the importance of cytokine and biomarker profiling in peri-implant tissue responses, especially in relation to host-modulating factors such as smoking or systemic inflammation.[1] Therefore, there is controversy toward the consensus regarding the long-term impact of cigarette smoking on dental implants.

More recently, cytokine levels in the PISF have been studied for their potential as diagnostic biomarkers for peri-implant disease.[5] A systematic review of 18 studies by Duarte et al has indicated that proinflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-12, IL-17 and tumor necrosis factor (TNF)-α are elevated in patients with peri-implant disease.[5] Studies have attempted to assess the impact of cigarette smoking on the levels of PISF cytokines around healthy[7] as well as those affected by peri-implantitis.[8] Results from these and other studies suggest that, as indicated by the increased level of PISF cytokines, smoking may increase inflammation in healthy implants or exaggerate the inflammation initiated by peri-implant disease.[7] [8] [9] [10] The objectives of this systematic review are to ascertain whether cigarette smoking has an impact on the cytokine profile in the PISF in healthy and diseased dental implants. This review will also focus on investigating the efficacy of periodontal therapy in reducing peri-implant inflammation as indicated by lowering of cytokine levels among smokers in comparison to NS.

 

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Materials and Methods

Focused Questions

The review was conducted using the Preferred Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.[11] The PRISMA checklist is provided in the Supplementary file. The review was not registered on PROSPERO. Using the Participants, Intervention, Control and Outcomes (PICO) principal,[11] the following questions were constructed:

1. In clinically healthy and diseased implants, what is the effect of cigarette smoking on the peri-implant cytokine profile when compared with NS?

2. What is the effect of periodontal therapy on peri-implant cytokines in smokers when compared with NS?

 

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Literature Search

Before commencing the literature search, inclusion and exclusion criteria were determined. The following types of studies were included: (1) studies comparing peri-implant cytokines in smokers and NS, (2) prospective clinical studies (randomized controlled trials, cross-sectional studies, case–control, observational studies), (3) studies in English. The following items were excluded: (1) reviews, (2) letters to the editor and commentaries, (3) animal and cell studies, (4) case reports and series.

The literature search was conducted by two authors. An electronic search was conducted on the following databases and registers: PubMed/Medline, Embase, Scopus, ISI Web of Science, Google Scholar, CENTRAL, and ClinicalTrials.gov. The following MeSH terms were used: ((dental implants) or (oral implants)) and ((cigarette) or (cigar) or (smoking) or (smokers) or (tobacco) or (nicotine)) and ((cytokine) or (chemokine) or (biomarker)) and ((peri-implant crevicular fluid) or (peri-implant sulcular fluid) or (gingival crevicular fluid) or (peri-implant)). The reference lists of the included articles were read to find any additional articles meeting our inclusion criteria. The following journals were hand-searched: Journal of Periodontology, Periodontology 2000, Journal of Clinical Periodontology, Clinical Oral Implants Research, Journal of Dental Research, Clinical Implant Dentistry and Related Research, Journal of Prosthetic Dentistry, Journal of Prosthodontic Research, Journal of Periodontal Research, International Journal of Oral and Maxillofacial Implants, International Journal of Prosthodontics and Cytokine. The inter-examiner reliability (kappa) score was calculated, and any disagreements were solved by discussion. The screening process was performed on the online platform Covidence. The PRISMA flow diagram of the literature search process is presented in [Fig. 1].

Fig. 1 PRISMA flow diagram for the literature search employed for this review.

 

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Data Extraction

Data was extracted independently and in duplicate by two investigators, M.A. and S.N., into two separate tables using Microsoft Excel. The first table ([Table 1]) focused on the following general characteristics of the included studies: authors, year and type of study, country in which the study was conducted, number of patients, age (mean and/or range) of the participants, number of implants studied, number of female participants, criteria of peri-implant disease or health inclusion and sites, and depth of volume of PISF collected. The second table ([Table 2]) focused on the following variables and parameters: study groups, cytokines analyzed or measured, details of any interventions performed, clinical/radiophonic peri-implant outcomes, and cytokine outcomes. We defined healthy implants as those having a periodontal pocket depth (PPD) less than 4 mm, and those having 4 mm PPD were classified as diseased implants. If no PPD information was available, we classified the population as described narratively by the study.

Table 1 General characteristics of the studies included in this review

No.	Study (author(s), year)	Country	Study design	Patients (n)	Age (range, mean in years)	Implants (n)	Females (n and/or %)	Peri-implant disease/health criteria	PISF sample site, depth, and volume
1	Tatli et al,[7] 2013	Türkiye	Cross-sectional	60	44.73 y	60	n = 30	PID/PD criteria NR Patients with regular recall and good OH	Duration: 30 s Depth NR
2	Ata-Ali et al,[21] 2016	Spain	Cross-sectional	29	63.6 y	74	58.1%	Only healthy implants included (PPD < 4 mm)	NR
3	Negri et al,[22] 2016	Brazil	Cross-sectional	48	52.5 y	NR	n = 18	Only healthy implants included (PPD < 4 mm)	Sites: M, D, B, L Duration: NR Depth: NR
4	Akram et al,[8] 2018	Pakistan	Cross-sectional	131	46.2 y	173	NR	Active PID/PD and healthy implants included (PID criteria: PPD > 4 mm)	NR
5	AlQahtani et al,[9] 2018	Saudi Arabia	Cross-sectional	160	41.9 y	253	n = 0	Active PID/PD and healthy implants included (PID criteria: PPD > 4 mm)	Depth 1–2 mm Duration: 30 s
6	AlQahtani et al,[10] 2019	Saudi Arabia	Cross-sectional	102	34 y	102	n = 0	Active PID/PD and healthy implants included (PID criteria: PPD > 4 mm)	NR
7	ArRejaie et al,[23] 2019	Saudi Arabia	Randomized controlled trial	98	39.6 y	159	n = 0	Active PID/PD and healthy implants included (PID criteria: PPD > 4 mm)	Depth: 1–2 mm Duration: 30 s
8	Al Deeb et al,[24] 2020	Saudi Arabia	Nonrandomized clinical trial	75	40.5 y	100	n = 4	Active PID/PD and healthy implants included (PID criteria: PPD > 6 mm, MBL > 3 mm)	NR
9	Al Deeb et al,[25] 2020	Saudi Arabia	Randomized controlled trial	71	29 y	111	n = 0	Implants with PID, CBL > 3 mm excluded	Depth: 1–2 mm Duration: 30 s
10	Dewan et al,[26] 2023	Saudi Arabia	Nonrandomized clinical trial	60	55.46 y	NR	n = 0	NR	Data not available

Abbreviations: CBL, crestal bone loss; PID, peri-implant disease; PD, periodontal disease; PPD, periodontal pocket depth; NR, not reported.

Table 2 Treatment groups, cytokine analytical techniques, methodology (cytokines measured and/or interventions conducted), and periodontal- and cytokine-related outcomes of the studies included in this review

No.	Study (author(s), year)	Study groups	Cytokine analysis technique	Intervention and follow-up	Cytokines assessed	Clinical/radiographic peri-implant outcomes or status	Cytokine outcomes
1	Tatli et al,[7] 2013	CS (n = 27 patients and implants CS (n = 33 patients and implants)	Periotron	N/A	IL-1β, TNF-α, PG-E2	GI (p < 0.05), PD (p < 0.05), MBL (p < 0.002) higher in CS. No statistically significant difference in PI (p > 0.05)	Higher levels of IL-1β, TNF-α, PG-E2 in CS. Stronger correlation between cytokine levels and periodontal parameters
2	Ata-Ali et al,[21] 2016	CS (n = 20 implants) NS (n = 54 implants)	Assay kits	N/A	IL-8, IL-1β, IL-6, IL-10, TNF-α	All implants clinically healthy	CS: Higher IL-1β, IL-6, IL-10 and TNF-α (p > 0.05). NS: IL-8 was higher (p > 0.05)
3	Negri et al,[22] 2016	CS (n = 25 patients) NS (n = 23 patients)	ELISA	N/A	INF-γ, IL-4, IL-17, IL-1β, IL-10, IL-6, IL-8, TNF-α, MMP-2, MMP-9, OPG, OC, OPN, RANKL, TGF-β, ICTP	All implants clinically healthy	Lower levels of OPG, IL-8 and TNF-α (p < 0.05) and higher levels of ICTP (p < 0.05) in CS. All cytokines were lower in smokers (p > 0.05) but no significant difference in the ratio of anti/pro-anti-inflammatory cytokine ratios between groups. TH1:TH2 ratio was higher in smokers (p < 0.05)
4	Akram et al,[8] 2018	CS (n = 44 patients) VS (n = 42 patients) NS (n = 45 patients) n, implants NR	ELISA	N/A	IL-1β, MMP-9	Both CS and VS had worse CBL, and PI (p < 0.05) compared to NS. BOP was higher in NS and VS than in CS (p < 0.05); BOP higher in VS than in NS (p < 0.05)	IL-1β and MMP-9 were higher in CS and VS compared to NS (p < 0.05). No difference in cytokine levels between CS and VS
5	AlQahtani et al,[9] 2018	CS (n = 40 patients; n = 71 implants) WS (n = 40 patients; n = 65 implants) VS (n = 40 patients, 62 implants) NS (n = 40 patients, 55 implants)	ELISA	N/A	TNF-α, IL-6, IL-1β	Mean PI, PPD > 4 mm, RBL were higher in CS, WS, VS compared to NS (p < 0.05)	Levels of TNF-α, IL-6, IL-1β in CS, VS, WS higher compared to NS (p < 0.05). TNF-α, IL-6, IL-1β higher in CS and WS compared to VS (p < 0.05)
6	AlQahtani et al,[10] 2019	CS (n = 35 patients and implants) WS (n = 33 patients and implants) VS (n = 34 patients and implants) CS (n = 35 patients and implants)	ELISA	N/A	Cotonine	PPD > 4 mm was significantly higher in CS, WS, VS groups compared to NS (p < 0.05). Higher BOP in NS (n < 0.05)	Cotinine levels higher in CS and CS than in VS, WS, and NS (n < 0.05)
7	ArRejaie et al,[23] 2019	CS (n = 32 patients, n = 59 implants) VS (n = 31 patients, n = 49 implants) NS (n = 32, n = 51 implants)	ELISA	N/A	IL-1β, MMP-9	MBL higher in CS than VS and NS (p < 0.01). PI and PPD > 4 mm higher in CS and VS (p < 0.01). Higher BOP in NS (p < 0.05)	MMP-9 (p < 0.001) and IL-1β (p < 0.01) higher in CS and VS. Positive correlation between MMP-9 (p < 0.05) and IL-1β (p < 0.005) with MBL in CS. Positive correlation between IL-1β and MBL in VS (p < 0.005)
8	Al Deeb et al,[24] 2020	CS (n = 25 patients, n = 34 implants) VS (n = 25 patients, n = 28 implants) NS (n = 25 patients, n = 38 implants)	ELISA	aPDT + SRP Evaluated 3 and 6 mo after treatment	RANK-L, OPG	BOP in VS and NS reduced significantly at just 3 months after aPDT + SRP (p < 0.05). CS showed a significant reduction only after 6 mo (p < 0.05)	Reduction in RANKL observed only in NS 3 and 6 months aPDT + SRP (p < 0.05). No effect of aPDT + SRP on cytokines in NS and VS
9	Al Deeb et al,[24] 2020	CS (n = 25 patients, n = 36 implants) VS (n = 21 patients, n = 32 implants) NS (n = 21 patients, n = 43 implants)	ELISA	aPDT + SRP Evaluated at baseline and 12 wk after treatment	MMP-8, TNF-α	Reduction in PI and PPD observed in all groups at baseline and 12 wk (p < 0.001). BOP increased more significantly in CS and VS groups than in NS (p < 0.05)	Reduction in MMP-8 and TNF-α observed in all groups at baseline and 12 wk. aPDT + SRP had the highest reduction in MMP-8 and TNF-α in NS (p < 0.01)
10	Dewan et al,[26] 2023	CS with PID (n = 2 NS with PID (n = 20) NS without PID (n = 20) n, implants NR	ELISA	N/A	suPAR, TNF-α	CBL higher in CS with and without PID than NS without peri-implantitis (p < 0.01). CBL higher in CS with PID than NS with and without PID (p < 0.01)	suPAR and TNF-α higher in CS with PID and NS with PID than NS without PID (p < 0.01). Positive correlation between PD and suPAR/TNF-α in CS with PID (p < 0.01)

Abbreviations: aPDT, antimicrobial photodynamic therapy; CS, cigarette smokers; IL, interleukin; INF, interferon; MMP, matrix metalloproteinase; NS, non-smokers; OC, osteocalcin; OPG, osteoprotegerin; OPN, osteopontin; PG-E2, prostaglandin E2; RANKL, receptor activator of NF-kappaB ligand; SRP, scaling and root planing; STU, smokeless tobacco users; suPAR, soluble urokinase plasminogen activator receptor; TGF, transforming growth factor; TNF, tumor necrotic factor; VS, vaping cigarette users; WS, water-pipe smokers.

 

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Quantitative Analysis

The standardized mean differences of the cytokines that were assessed in multiple studies were selected for quantitative analysis using a random effect model using the RevMan 5.4 software. Confidence interval was set at 95% to evaluate the statistical significance (p > 0.05) between the differences in cytokine levels among smokers and NS. I ² statistic was performed to determine the heterogeneity between the studies.

 

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Quality Assessment of the Studies

A modified version of the critical appraisal skills program (CASP)[12] was employed to carry out the assessment for quality and risk of bias. Briefly, different aspects of the study design, methodology, reporting of results, and applicability of results were evaluated. Depending on the subjective score received, each study was assigned a low, moderate, or high score for quality.

 

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Results

Results of the Literature Search

Primary search resulted in a total of 1,592 records after the removal of 5 duplicates and exclusion of 345 due to other reasons. A further 1,271 items were excluded based on titles and abstracts. Therefore, 321 articles were screened for eligibility. A total of 298 further articles were included because they did not address the focused questions constructed for this systematic review. Therefore, full texts of 33 records were sought for retrieval. Five review articles[4] [5] [13] [14] [15]—one study in which no cigarette smokers (CS) were included,[16] two studies in which there was no comparison made between peri-implant cytokines among smokers and NS,[17] [18] and two studies in which peri-implant cytokines were not evaluated[19] [20]—were all excluded. With a further exclusion of 13 articles due to other reasons, 10 articles were selected for qualitative analyses for this systematic review.[7] [8] [9] [10] [21] [22] [23] [24] [25] [26] No additional studies were found up on scanning the references of the included studies or on hand-searching. The overall inter-examiner reliability (kappa [κ]) score was calculated as 0.89.

 

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General Characteristics of Included Studies

Six studies were cross-sectional studies,[7] [8] [9] [10] [21] [22] two studies were randomized controlled trials,[23] [24] and two were nonrandomized clinical studies.[25] [26] Six studies were conducted in Saudi Arabia[9] [10] [23] [24] [25] [26] and one each in Turkey[7] Pakistan,[8] Brazil,[22] and Spain.[21] Number of participants ranged from 29 to 160, with a total of 774 patients.[8] [9] [10] [21] [22] [23] [24] [25] [26] The overall number of implants analyzed were 1,122. The mean age of the participants ranged between 29 and 63.6 years.[8] [9] [10] [21] [22] [23] [24] [25] [26] Number of implants evaluated ranged between 74 and 253[7] [9] [10] [21] [22] [23] [24] [25] and in two studies, the number of implants were not reported.[8] [26] Overall, peri-implant cytokines around 1,122 dental implants placed were measured.[7] [9] [10] [21] [22] [23] [24] [25] In five studies, females were not included in the study groups.[9] [10] [23] [24] [26] The reported number of females ranged between 4 and 30.[7] [22] [25] In one study, the proportion of females was expressed as a percentage which was 58.1%,[21] and the gender of included participants was not stated in one study.[8] In three studies, peri-implant cytokines were measured around clinically healthy implants which were defined as having a pocket depth of less than or equal to 4 mm.[7] [21] [22] In five studies, peri-implant cytokines were measured around healthy and diseased dental implants[9] [10] [23] [24] [25] and in two studies, peri-implant cytokines were measured only at healthy implant sites or around implants that had been regularly maintained by peri-implant therapy.[7] [21] [22] In one study, the implant health or disease status was not described.[26] In four studies, the PISF collection and analysis technique were not described.[8] [10] [21] [24] On the other hand, in the studies that did report details of PISF analysis, the depth ranged between 1 and 2 mm and the duration was 30 second,[7] [9] [22] [23] [24] and, in one study, only the collection sites (mesial, distal, buccal, and lingual) at the implants were stated.[22] In all studies except two, in which cytokine assay kits and Periotron were used,[7] [21] ELISA was used for cytokine analysis.[8] [9] [10] [22] [23] [24] [25] [26]

 

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Study Groups and Interventions

In two studies, PISF cytokines were compared between CS and NS.[21] [22] In four studies, the PISF cytokines were compared between CS, vape users (VS), and NS.[8] [23] [24] [25] In two studies in addition to CS, VS, and NS, PISF was also analyzed in water-pipe smokers (WS).[9] [10] In one study, the PISF cytokine levels in NS with and without peri-implantitis were compared with those in CS.[26] Antimicrobial periodontal therapy (aPDT) (with nonsurgical periodontal therapy) was used in clinical trials as interventions, and the cytokines were measured immediately posttreatment.[24] [25] In the remaining studies, no intervention was performed.[8] [9] [10] [21] [22] [23] [26]

 

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Peri-implant Cytokines Measured

IL-1β was measured in four studies,[8] [9] [21] [22] TNF-α[9] [21] [22] [26] was evaluated in five studies,[9] [21] [22] [25] [26] IL-6 was assessed in three studies,[9] [21] [22] IL-8 was measured in two studies,[21] matrix metalloproteinase (MMP)-9 was measured in three studies,[8] [22] [23] and RANKL/OPG (receptor activator of nuclear factor kappa-β ligand/osteoprotegerin) ratios were determined in two studies.[22] [25] Osteopontin (OPN), osteocalcin (OC), transforming growth factor (TGF)-β, type I collagen carboxyterminal telopeptide (ICTP), interferon (INF)-γ, and MMP-2 levels were measured in one study.[22] Cotonine,[9] MMP-8,[24] and soluble urokinase plasminogen activator receptor (suPAR)[26] levels were measured in one study each.

 

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Peri-implant Health in Smokers and Non-smokers

In two studies, peri-implant and periodontal tissues were diagnosed as healthy in CS and NS[21] [22] because only clinically healthy implants were included and there were no differences in the periodontal parameters between CS and NS. In other studies, there was a statistically significantly higher bone loss, plaque index, and PPD in CS when compared with NS and all other types of smoking.[8] [9] [10] [21] [22] [23] [26] On the other hand, during active peri-implant disease, BOP was significantly higher in NS and VS, compared with CS.[8] [9] [23]

 

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Peri-implant Cytokine Profile in Smokers and Non-smokers

In one study, IL-1β, IL-6, IL-10, and TNF-α around clinically healthy implants were higher in CS than in NS, but the difference was not statistically significant.[21] In another study, the levels of OPG, IL-8, and TNF-α were significantly lower when compared with NS.[22] Furthermore, in the same study, TH1/TH2 cytokine ratios were higher in CS than in NS.[22] During peri-implant disease, the levels of proinflammatory cytokines and biomarkers IL-1β, IL-6, TNF-α, MMP-9, MMP-8, cotinine, and suPAR were markedly higher in CS than in NS.[8] [9] [10] [23] [26]

 

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Effect of Periodontal Therapy on Peri-implant Cytokine Levels and Periodontal Parameters in Smokers and Non-smokers

aPDT and scaling root planing (aPDT + SRP) resulted in a significant reduction in bleeding on probing (BOP) among NS and VS just 3 months after treatment, but BOP reduction was observed only at 6 months posttreatment in CS.[25] In another study, a significant reduction in PI and pocket depth was observed in all groups regardless of the smoking status, but a higher BOP was observed 12 weeks posttreatment in smokers.[25]

In one study, aPDT + SRP was successful in significantly reducing RANKL levels only in non-smoker participants when compared with CS and VS[25] up to 6 months posttreatment. On the other hand, aPDT and SRP were able to reduce levels of MMP-8 and TNF-α significantly after 12 weeks when compared with baseline, regardless of the smoking status,[24] but periodontal therapy had a more statistically profound impact on MMP-8 and TNF-α in NS.[24]

 

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Correlation between Cytokine Levels and Peri-implant Bone Loss

The correlation between cytokine levels and peri-implant bone loss or pocket depth was evaluated in two studies.[23] [26] A positive correlation was observed between peri-implant IL-1β and MMP-9 levels with marginal bone loss in one study[23] and a similar association was observed between pocket depth and suPAR/TNF-α levels in CS with peri-implant disease.[26]

 

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Results of the Meta-analysis

Meta-analysis of studies in which the peri-implant cytokines around healthy implants were measured revealed that compared with NS, the overall effect of smoking on cytokine levels is not statistically significant (IL-1β: p = 0.36, TNF-α: p = 0.95, IL-6: p = 0.88, IL-8: p = 0.23). On the other hand, in peri-implant disease, smoking has a more statistically significant effect on the peri-implant levels of IL-1β (p < 0.00001) and MMP-9 (p < 0.00001). The studies that had measured IL-1β and TNF-α during peri-implantitis had high degrees of heterogeneity as indicated by I ² levels of 93 and 86%, respectively. No heterogeneity was present between studies that had measured MMP-9 during peri-implantitis, but the data were extracted from only two studies. TNF-α levels were not significantly impacted by the smoking status of the patients. In the majority of the studies included in the meta-analysis of cytokine levels during peri-implantitis and in healthy implants, there was a significant level of heterogeneity between the studies. The results of the meta-analysis of studies conducted on healthy implants are presented in [Fig. 2] and those focusing on peri-implant cytokines during peri-implantitis are presented in [Fig. 3]. The results are also presented in [Tables 3] and [4].

Table 3 A summary of the meta-analysis results of the comparison of peri-implant cytokine levels between smokers and non-smokers around clinically healthy implants

Cytokine	No. of studies	Patients (N)	SMD	95% CI	Heterogeneity (I²)
IL-1β	3	137	0.44	[−0.50, 1.39]	84%
IL-6	2	77	0.11	[−0.11, 1.51]	86%
IL-8	2	77	−0.53	[−1.40, 0.33]	64%
TNF-α	5	137	−0.03	[−1.01 to 0.95]	86%

Table 4 A summary of the meta-analysis results of the comparison of peri-implant cytokine levels between smokers and non-smokers around clinically diseased implants

Biomarker	No. of studies	Patients (N)	SMD	95% CI	Heterogeneity (I²)
IL-1β	3	233	3.86	[2.22, 5.51]	93%
TNF-α	3	137	−0.03	[−1.01, 0.95]	86%
MMP-9	2	153	3.51	[2.99, 4.02]	0%

Fig. 2 The results of the quantitative analysis of the studies conducted on healthy implants included in his review. IL-1β, interleukin-1β; IL-6, interleukin-6; interleukin-8; TNF-α, tumor necrosis factor-α.

Fig. 3 The results of the quantitative analysis of the studies conducted on diseased implants included in this review. IL-1β, interleukin-1β; MMP-9, matrix metalloproteinase-9; TNF-α, tumor necrosis factor-α.

 

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Results of the Quality Assessment

Quality assessment of the studies revealed that 9 out of 10 studies had several sources of methodological deficiencies and sources, and therefore received an overall score of “low.”[7] [9] [10] [21] [22] [23] [24] [25] [26] One study received an overall score of “moderate.”[8] Randomization was clearly defined in only one study.[22] Five studies did not adequately account for the participants.[7] [22] [24] [25] [26] In two studies, only the investigators were blinded[10] [22] and one study blinded both the investigators and the analysts.[8] Similar baseline variables were described adequately in only four studies.[7] [8] [25] [27] All studies described similar quality of care or intervention in all groups, adequate reporting and value of intervention or diagnostic test.[7] [8] [9] [10] [21] [22] [23] [24] [25] [26] However, since all studies performed their investigation in single geographical locations, none of the results could be applied to other demographics or countries. Additionally, none of the studies performed or described a benefit/harm assessment or cost-effectiveness analysis of cytokine measurements or interventions. The results of the quality assessment are provided in [Table 5].

Table 5 The results of the quality assessment of the included studies using the Critical Appraisal Skills Program (CASP) tool

Study (author(s), year)	Focused research question	Randomization	Participants accounted for	Blinding		Baseline variables/similarity of groups	Similarity of care	Treatment of study groups	Reporting of outcomes/intervention effects	Precision of treatment effects	Benefit/Harm assessment	Applicability	Value of intervention/diagnostic test	Overall quality
				Investigators	Analysts
Tatli et al,[7] 2013	Yes	No	No	No	No	Yes	Yes	Yes	Yes	No	No	No	Yes	Low
Ata-Ali et al,[21] 2016	Yes	No	Yes	No	No	No	Yes	Yes	Yes	No	No	No	Yes	Low
Negri et al,[22] 2016	Yes	Yes	No	Yes	No	No	Yes	Yes	Yes	No	No	No	Yes	Low
Akram et al,[8] 2018	Yes	No	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No	No	Yes	Moderate
AlQahtani et al,[9] 2018	Yes	No	Yes	No	No	Yes	Yes	Yes	Yes	No	No	No	Yes	Low
AlQahtani et al,[10] 2019	Yes	No	Yes	Yes	No	No	Yes	Yes	Yes	No	No	No	Yes	Low
ArRejaie et al,[23] 2019	Yes	Not clear	Yes	No	No	No	Yes	Yes	Yes	No	No	No	Yes	Low
Al Deeb et al,[24] 2020	Yes	No	No	No	No	No	Yes	Yes	Yes	No	No	No	Yes	Low
Al Deeb et al,[25] 2020	Yes	No	No	No	No	Yes	Yes	Yes	Yes	No	No	No	Yes	Low
Dewan et al,[26] 2023	Yes	No	No	No	No	No	Yes	Yes	Yes	No	No	No	Yes	Low

 

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Discussion

The aim of this systematic review was to assess the overall impact of cigarette smoking on the PISF cytokine profile in comparison to that in NS in clinically healthy implants as well as those experiencing peri-implant disease. The results of the studies included in this review indicate that smokers have a cytokine profile that has higher levels of proinflammatory cytokines even when the implants are clinically healthy[21] [22] as well as during peri-implant disease.[8] [9] [10] [23] [26] Two studies also indicate that scaling and root planing, even when combined with antimicrobial photodynamic therapy, is less effective in reducing peri-implant inflammation in smokers when compared with NS.[24] [25] In smokers with clinically healthy implants, proinflammatory cytokines such as TNF-α, IL-8, and IL-4 are significantly higher in comparison to NS.[22] This highlights the potential for subclinical inflammation to exist even in the absence of overt clinical signs, which may predispose patients to accelerated disease progression if not identified and addressed early. Clinicians should therefore consider cytokine profiling or risk-based assessment tools in the routine follow-up of smokers, even when implants appear clinically stable.[1] [35] This suggests that even when implants are clinically “healthy,” peri-implant tissues are chronically inflamed, not only necessitating a more robust peri-implant maintenance program but also warranting ceasing or reducing cigarette smoking.

In the studies in which PISF cytokines were measured during peri-implant disease, a general trend of an increase in proinflammatory cytokines such as IL-1β, IL-6, MMP-8, MMP-9, and TNF-α was observed.[8] [9] [10] [23] [26] This suggests that smoking worsens the destruction of peri-implant tissues by upregulating these cytokines. Indeed, previous studies on gingival crevicular fluid cytokine profiles in inflamed periodontal tissues have observed similar effects of smoking on cytokines and other biomarkers of periodontitis around natural teeth during disease and in health.[28] [29] Dental implants, being foreign bodies, induce a chronic inflammatory response which can then contribute to periodontal disease initiated by poor oral hygiene, cigarette smoking, and other factors[30]; mechanical debridement with or without surgery should be strongly advocated in CS with dental implants. An increase in RANKL/OPG is associated with increased severity of periodontal disease and bone loss.[31] Studies included in this review indicate that around diseased as well as healthy dental implants, smoking stimulates higher levels of RANKL, which are associated with increased osteoclastic activity, which in turn may contribute to worse peri-implant bone loss compared with NS.[22] [25] However, owing to a small sample size and several methodological limitations in these studies, further research is required to explore this observation.

Only one study mentioned the average time the dental implants had been in function for (in smokers: 39.56 ± 5.81 months; in NS: 38.64 ± 4.13 months) and it revealed that peri-implant IL-1β may become elevated in smokers more significantly when compared with NS,[7] even in well-maintained implant recall patients. Therefore, future studies should focus on peri-implant cytokines around dental implants that have been in function for a longer time to assess the long-term implications of smoking on peri-implant inflammation. The meta-analysis of studies that had assessed the peri-implant cytokines during peri-implantitis reveals that smokers have significantly higher levels of IL-1β compared with NS, a cytokine that has been implicated in the pathogenesis of periodontal disease.[32] This suggests that smoking aggravated the intensity of peri-implant inflammation as indicated by a higher bone loss around dental implants and a higher rate of implant failure observed in smokers previously.[33] The higher magnitude of peri-implant bone loss in smokers could be explained by the higher levels of the osteoclastic RANKL observed in clinically healthy dental implants compared with NS.[22] MMPs play an important role in the pathogenesis in periodontal disease because they contribute toward the extracellular matrix during inflammation[34] and two studies that were included in this review observed that there is a direct correlation of marginal bone loss around implants and MMP-9, as well as IL-1β levels, suggesting that upregulation of MMP-9 may be one of the ways cigarette smoking contributes to peri-implant bone loss.[23]

There are some limitations in this systematic review. Although quantitative analyses were performed, only a few of the studies could be included in them. The overall sample size included in the meta-analysis was small, and there was significant heterogeneity within the studies as evidenced by the high I ² statistics, which prevented us from drawing any meaningful conclusions from the majority of the studies. Within the included studies, the lack of standardized cytokine measurement is perhaps the most crucial factor that may have influenced the outcomes. Furthermore, there was significant variability in age, gender (mostly men were included across the studies), periodontal/implant health status, number of cigarettes smoked per day, and the time for which the implants had been in function—all of which may have further contributed to the heterogeneity between the studies. Furthermore, a lack of blinding and small sample sizes may have influenced the outcomes of the included studies. Moreover, other (often undiagnosed) systemic diseases such as diabetes may also influence the levels of periodontal cytokines.[35] From a clinical perspective, it is essential to recognize that elevated proinflammatory cytokine levels may exist even in the absence of clinical signs of peri-implant disease. This may call for more rigorous maintenance protocols in smokers, as suggested in biomarker-driven implant monitoring strategies.[1] Therefore, future studies should account for these confounding variables to better understand the role of cytokines in peri-implant health and disease.

 

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Conclusion

Within the limits of this systematic review, it may be concluded that cigarette smoking aggravates peri-implantitis by influencing the cytokine profile to proinflammatory. In healthy dental implants, this effect is less profound, and there is no significant distinction of cytokine profiles between healthy and diseased dental implants. Furthermore, periodontal therapy may be less effective in reducing peri-implant inflammation in smokers in comparison to NS. It is recommended that smokers who have received dental implants adopt a more robust implant maintenance recall owing to the consistently raised proinflammatory peri-implant cytokine profile. Cessation of cigarette smoking in these individuals is also encouraged. Lastly, due to high heterogeneity and generally low quality of the included studies, the conclusions should be interpreted cautiously. A clearer call for well-designed prospective studies is warranted.

 

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Conflict of Interest

None declared.

Ethical Approval

Institutional Review Board statement: Not applicable.

Data Availability Statement

The data supporting this study's findings are available from the corresponding author upon reasonable request.

Authors' Contributions

M.A. and S.N.: conceptualization, writing manuscript, and methodology. H.K.K., A.S.: data extraction. A.B.M.R.A., M.N.: quality assessment.

• References

• 1 Rajasekar A, Varghese SS. Microbiological profile in periodontitis and peri-implantitis: a systematic review. J Long Term Eff Med Implants 2022 32. (04)
• 2 Dreyer H, Grischke J, Tiede C. et al. Epidemiology and risk factors of peri-implantitis: a systematic review. J Periodontal Res 2018; 53 (05) 657-681
• 3 Rokaya D, Srimaneepong V, Wisitrasameewon W, Humagain M, Thunyakitpisal P. Peri-implantitis update: risk indicators, diagnosis, and treatment. Eur J Dent 2020; 14 (04) 672-682
• 4 Javed F, Rahman I, Romanos GE. Tobacco-product usage as a risk factor for dental implants. Periodontol 2000 2019; 81 (01) 48-56
• 5 Duarte PM, Serrão CR, Miranda TS. et al. Could cytokine levels in the peri-implant crevicular fluid be used to distinguish between healthy implants and implants with peri-implantitis? A systematic review. J Periodontal Res 2016; 51 (06) 689-698
• 6 Romanos GE, Gaertner K, Aydin E, Nentwig GH. Long-term results after immediate loading of platform-switched implants in smokers versus nonsmokers with full-arch restorations. Int J Oral Maxillofac Implants 2013; 28 (03) 841-845
• 7 Tatli U, Damlar I, Erdoğan O, Esen E. Effects of smoking on periimplant health status and IL-1β, TNF-α, and PGE2 levels in periimplant crevicular fluid: a cross-sectional study on well-maintained implant recall patients. Implant Dent 2013; 22 (05) 519-524
• 8 Akram Z, Vohra F, Bukhari IA, Sheikh SA, Javed F. Clinical and radiographic peri-implant parameters and proinflammatory cytokine levels among cigarette smokers, smokeless tobacco users, and nontobacco users. Clin Implant Dent Relat Res 2018; 20 (01) 76-81
• 9 AlQahtani MA, Alayad AS, Alshihri A, Correa FOB, Akram Z. Clinical peri-implant parameters and inflammatory cytokine profile among smokers of cigarette, e-cigarette, and waterpipe. Clin Implant Dent Relat Res 2018; 20 (06) 1016-1021
• 10 AlQahtani F, Alqahtani M, Albaqawi AH, Al-Kheraif AA, Javed F. Comparison of cotinine levels in the peri-implant sulcular fluid among cigarette and waterpipe smokers, electronic-cigarette users, and nonsmokers. Clin Implant Dent Relat Res 2019; 21 (04) 702-707
• 11 Moher D, Altman DG, Liberati A, Tetzlaff J. PRISMA statement. Epidemiology 2011; 22 (01) 128 , author reply 128
• 12 Long HA, French DP, Brooks JM. Optimising the value of the critical appraisal skills programme (CASP) tool for quality appraisal in qualitative evidence synthesis. Res Methods Med Health Sci 2020; 1 (01) 31-42
• 13 Bielemann AM, Marcello-Machado RM, Del Bel Cury AA, Faot F. Systematic review of wound healing biomarkers in peri-implant crevicular fluid during osseointegration. Arch Oral Biol 2018; 89: 107-128
• 14 Bormann KH, Stühmer C, Z'Graggen M, Kokemöller H, Rücker M, Gellrich NC. IL-1 polymorphism and periimplantitis. A literature review. Schweiz Monatsschr Zahnmed 2010; 120 (06) 510-520
• 15 Greenstein G, Hart TC. Clinical utility of a genetic susceptibility test for severe chronic periodontitis: a critical evaluation. J Am Dent Assoc 2002; 133 (04) 452-459 , quiz 492–493
• 16 Al-Aali KA, Alrabiah M, ArRejaie AS, Abduljabbar T, Vohra F, Akram Z. Peri-implant parameters, tumor necrosis factor-alpha, and interleukin-1 beta levels in vaping individuals. Clin Implant Dent Relat Res 2018; 20 (03) 410-415
• 17 Chaparro A, Beltrán V, Betancur D. et al. Molecular biomarkers in peri-implant health and disease: a cross-sectional pilot study. Int J Mol Sci 2022; 23 (17) 9802
• 18 Al-Khureif AA, Mohamed BA, Siddiqui AZ, Hashem M, Khan AA, Divakar DD. Clinical, host-derived immune biomarkers and microbiological outcomes with adjunctive photochemotherapy compared with local antimicrobial therapy in the treatment of peri-implantitis in cigarette smokers. Photodiagnosis Photodyn Ther 2020; 30: 101684
• 19 AlJasser R, Zahid M, AlSarhan M, AlOtaibi D, AlOraini S. The effect of conventional versus electronic cigarette use on treatment outcomes of peri-implant disease. BMC Oral Health 2021; 21 (01) 480
• 20 Sayardoust S, Omar O, Thomsen P. Gene expression in peri-implant crevicular fluid of smokers and nonsmokers. 1. The early phase of osseointegration. Clin Implant Dent Relat Res 2017; 19 (04) 681-693
• 21 Ata-Ali J, Flichy-Fernández AJ, Alegre-Domingo T, Ata-Ali F, Peñarrocha-Diago M. Impact of heavy smoking on the clinical, microbiological and immunological parameters of patients with dental implants: a prospective cross-sectional study. J Investig Clin Dent 2016; 7 (04) 401-409
• 22 Negri BM, Pimentel SP, Casati MZ, Cirano FR, Casarin RC, Ribeiro FV. Impact of a chronic smoking habit on the osteo-immunoinflammatory mediators in the peri-implant fluid of clinically healthy dental implants. Arch Oral Biol 2016; 70: 55-61
• 23 ArRejaie AS, Al-Aali KA, Alrabiah M. et al. Proinflammatory cytokine levels and peri-implant parameters among cigarette smokers, individuals vaping electronic cigarettes, and non-smokers. J Periodontol 2019; 90 (04) 367-374
• 24 Al Deeb M, Alresayes S. A Mokeem S, et al Clinical and immunological peri-implant parameters among cigarette and electronic smoking patients treated with photochemotherapy: a randomized controlled clinical trial. Photodiagnosis Photodyn Ther 2020; 31: 101800
• 25 Al Deeb M, Alresayes S. A Mokeem S, et al Clinical peri-implant health and biological bone marker levels in tobacco users treated with photodynamic therapy. Photodiagnosis Photodyn Ther 2020; 31: 101821
• 26 Dewan H, Robaian A, Divakar DD, Hegde SMR, Shankar SM, Poojary B. Levels of peri-implant sulcular fluid levels of soluble urokinase plasminogen activator receptor and TNF-α among cigarette smokers and non-smokers with peri-implantitis. Technol Health Care 2023; 31 (01) 1-9
• 27 AlQahtani Q, Zaky SH, Patil A, Beniash E, Ray H, Sfeir C. Decellularized swine dental pulp tissue for regenerative root canal therapy. J Dent Res 2018; 97 (13) 1460-1467
• 28 BinShabaib M, ALHarthi SS, Akram Z. et al. Clinical periodontal status and gingival crevicular fluid cytokine profile among cigarette-smokers, electronic-cigarette users and never-smokers. Arch Oral Biol 2019; 102: 212-217
• 29 Dutra TP, Sacramento CM, Nagay BE. et al. Do smokers have a different gingival crevicular fluid cytokine/chemokine profile than nonsmokers in clinically healthy periodontal sites? A systematic review and meta-analysis. Clin Oral Investig 2022; 26 (02) 1183-1197
• 30 Zhang D. et al. Dealing with the foreign-body response to implanted biomaterials: strategies and applications of new materials. Adv Funct Mater 2021; 31 (06) 2007226
• 31 Yewale M, Agnihotri R. The role of bone-specific biomarkers in chronic periodontitis diagnosis and treatment outcomes - a systematic review. Evid Based Dent Published online March 16, 2022;
• 32 Boström L, Linder LE, Bergström J. Smoking and GCF levels of IL-1β and IL-1ra in periodontal disease. J Clin Periodontol 2000; 27 (04) 250-255
• 33 Alfadda SA. Current evidence on dental implants outcomes in smokers and nonsmokers: a systematic review and meta-analysis. J Oral Implantol 2018; 44 (05) 390-399
• 34 Franco C, Patricia HR, Timo S, Claudia B, Marcela H. Matrix metalloproteinases as regulators of periodontal inflammation. Int J Mol Sci 2017; 18 (02) 440
• 35 Javed F, Al-Askar M, Al-Hezaimi K. Cytokine profile in the gingival crevicular fluid of periodontitis patients with and without type 2 diabetes: a literature review. J Periodontol 2012; 83 (02) 156-161

Publication History

Article published online:
11 September 2025