Long-Term Prognosis of Peri-Implantitis Treatment: A Systematic Review of Prospective Trials with More Than 3 Years of Follow-Up

Featured Application: Regenerative approaches for treatment of peri-implantitis lead to favorable long-term clinical outcomes and survival rate. Abstract: A multitude of clinical trials have tested therapeutic approaches to treat peri-implantitis but there is still no consensus on what treatment modality leads to the most favorable clinical improvement and reduced implant loss. Therefore, the present systematic review reported on the long-term clinical and radiological outcomes after treatment of peri-implantitis with di ﬀ erent surgical approaches. A PICO question was deﬁned; manual and electronic searches were completed to screen for human prospective studies with at least 3 years of follow-up after surgical treatment of peri-implantitis. Analyses were performed using a random-e ﬀ ect model. Thirteen trials reported on 706 implants and 399 patients. Open ﬂap, resective and reconstructive approaches led to a probing depth reduction of 2.23, 2.25 and 3.78 mm with a survival rate of 84%, 90% and 95%, respectively. Reconstructive treatments were followed by an average of 2.34 mm of radiographic bone gain, ﬂap had negligible bone changes (0.11 mm) and resective approaches resulted in a mean bone loss of 0.5 mm. Large heterogeneity existed among studies for diagnostic criteria and decontamination modalities. Within the existing limitations, regenerative approaches for the treatment of peri-implantitis lead to advantageous long-term improvement of peri-implant tissues and higher implant survival rate. OFD: open flap debridement, SLA: sandblasted acid-etched surface, TPS: titanium plasma-sprayed surface. H.-L.W.; visualization, Z.C., M.V.R. and H.-L.W.; supervision: H.-L.W. and Z.C.; project administration: H.-L.W. All authors provided signiﬁcant contribution in the conception, data acquisition, data elaboration and writing. All authors have read and agreed to the published version of the manuscript.


Introduction
Peri-implantitis is a destructive inflammatory disease of soft and hard tissues surrounding dental implants [1]. Due to the large prevalence [2,3], accelerating pattern of progression [4], and unknown predisposing factors [5], peri-implantitis represents one of the unsolved challenges of the contemporary implant dentistry. Current evidence has shown non-surgical treatment of peri-implantitis to be ineffective with disease control in only 22% of treated cases [6,7], while surgical therapies are followed by more favorable treatment prognosis [8]. A 7 year study on reconstructive treatment of peri-implantitis reported 83% of implant survival rate [9] and a 2-11 year retrospective study showed 78% of implants with no further bone loss after resective treatment [10]. Over the years, different types of surgical interventions have been proposed, and no clear evidence exists to define a single most predictable approach [11]. Proposed treatments are complex combinations of mechanical devices, chemical agents,

Selection Process
The electronic and journal-based searches were conducted in accordance with the PRISMA principles [16] and yielded 314 and 15 additional reports, respectively, for a total of 329 records. During abstract evaluation, 283 references were excluded, and 46 articles were investigated in their full-text form. Furthermore, 27 articles were removed during the full-text investigation, while 19 articles from 13 prospective human clinical trials were included. Four trials [22][23][24][25] reported data from the same pool of patients in more than one publication and data were evaluated in order to keep from counting the same population twice. The analysis was therefore finalized on 13 prospective clinical trials ( Figure 1). Risk of bias of included studies was assessed according to the Cochrane Collaboration tool and reported in Table 1.

Discussion
The present systematic review integrated data from thirteen human long-term prospective clinical trials and provided weighted averages for clinical and radiographic outcomes after surgical treatment of peri-implantitis. Studies were grouped based on treatment modality and it was found that more favorable bone gain was noted with regenerative approaches, despite successful outcomes for PD reduction and implant survival rate being achieved in all treatment modalities.

Discussion
The present systematic review integrated data from thirteen human long-term prospective clinical trials and provided weighted averages for clinical and radiographic outcomes after surgical treatment of peri-implantitis. Studies were grouped based on treatment modality and it was found that more favorable bone gain was noted with regenerative approaches, despite successful outcomes for PD reduction and implant survival rate being achieved in all treatment modalities.
Previous systematic reviews on the topic have reported similar findings as the regenerative treatment of peri-implantitis was followed by 2.1 mm of bone fill in Chan et al. [38] and by 2.4 mm in Khoshkam et al. [39], which is very similar to the 2.3 mm of RBG reported in the present systematic review. As most of the peri-implantitis defects have infrabony components [40], regenerative therapies appear advantageous to obtain bone regeneration, and gain peri-implant attachment while minimizing probing depth. Roccuzzo et al. obtained a PD reduction of 3.4 mm and about 2 mm RBG using a regenerative protocol with bovine bone and connective tissue graft [9]. A recent study by Wang et al. used bone allograft and acellular dermal matrix membrane after decontamination with Erbium YAG (Er:YAG) laser and reported 2.25 mm of PD reduction and 1.18 mm of RBG [8]. Froum et al. implemented bovine bone with the use of PDGF or EMD and reported that 91% of the treated implants had 5.1 mm of PD reduction and 1.77 mm of RBG [29].
Regenerative approaches seem advantageous to reconstruct the lost supporting bone in infrabony defects. On the contrary, resective and flap approaches are best indicated for suprabony defects in non-esthetic areas. Berglundh et al. treated 95 implants with open flap debridement together with limited osteoplasty and reported a PD reduction of about 2.5 mm. The estimated probabilities of further bone loss related with residual PD so that the probability of no further bone loss was 83% for postsurgical PD shallower than 5 mm [10]. The same group reported how implants with minimally rough surfaces have 45% more probability to achieve treatment success after resective treatment if compared with moderately rough surfaces [41]. Heitz-Mayfield et al. advocated for open flap debridement without any bone recontouring or implant surface modification. As reported, a saline-soaked gauze was used to rub against the implant surfaces along with copious saline irrigation; in addition, a combination of two adjunctive antimicrobials (amoxicillin and metronidazole) was prescribed as an adjunctive therapy. Mean PD reduction was 2.1 and half of implants had less than 5 mm residual PD, no BoP and no further bone loss [30].
Flap and resective treatment modalities stress the importance of a post-surgical shallow probing depth; however, whether or not residual pockets after therapy represent a risk factor for recurrence of peri-implantitis remains unclear. Serino et al. concluded that residual pathological probing depth is an unfavorable prognostic factor [33]; however, Roos-Jansaker et al. and Heitz-Mayfield et al. reported that a stable peri-implant condition was maintained without correlation with pockets deeper than 5 mm [30,31]. It could be speculated that the presence of plaque and inflammation in the loci of deep pockets could be a prognostic factor for disease progression more accurate than PD alone; however, data from a 5-year randomized clinical trial (RCT) failed to demonstrate any association between peri-implantitis progression and clinical variables including plaque, BoP, and PD [31].
In the present analysis, direct comparisons among treatment groups were voluntarily avoided due to the high heterogeneity of available articles for inclusion criteria and re-treatment in the case of disease recurrence in the follow-up period. As for the inclusion criteria, most of the studies were designed before the publication of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. Therefore, their inclusion criteria follow different, more permissive, enrollment processes [17][18][19][20][21]. Following the directions of workgroup four of the 2017 World Workshop, peri-implantitis is diagnosed with: (i) presence of bleeding and/or suppuration on gentle probing. (ii) Increased probing depth compared to previous examinations. (iii) Presence of bone loss beyond crestal bone level changes resulting from initial bone remodeling, (iv) or with probing depths of ≥6 mm and bone levels ≥3 mm apical of the most coronal portion of the intraosseous part of the implant in the case of absence of baseline data. [1].
Another point of disagreement among authors is whether or not implants should be retreated during the follow-up in the case of disease recurrence. Roccuzzo et al. and Isehed et al. surgically retreated implants in the case of disease recurrence and provided data mixing those treated once with those treated more than once [9,14]. On the other hand, Schwarz et al. excluded retreated implants from the main statistical analysis [13,32]; similarly, Romeo et al. dismissed patients showing persistence of inflammation [36].
The large heterogeneity of existing studies might be used as a call to suggest more unitary directions for future research studies. Standardized inclusion criteria following the 2017 World Workshop appear to be of primary importance. In addition, authors should report data of implants not responding to the treatment with separate analyses, to increase the focus of literature on possible negative prognostic factors after treatment of peri-implantitis.

Conclusions
In the light of the discussed heterogeneity, surgical treatment of peri-implantitis following flap, resective or regenerative approaches improved peri-implant probing depth and survival rate three to seven years after surgical treatment of peri-implantitis. Regenerative therapies induced more favorable radiographic bone gain and biological outcomes.