The professional management of peri- implantitis A systematic review of randomised controlled trials.

Dr Chloe Harrington-Taylor

BDS Bris MJDF RCS eng PG Cert aesthetic/rest dent

A dissertation submitted to the University of Bristol in accordance with the requirements of the degree of Master of Dental Science by advanced study in Implantology in the Faculty of Oral and Dental Science.

The University of Bristol. July 2018.

Word count: 15, 872

The professional management of peri-implantitis- a systematic review. 1 Abstract

Background: Dental implants are a widely accepted treatment modality. Bacterial plaque accumulation around implants leads to inflammation of the peri-implant soft tissues. Unresolved inflammation may lead to progressive bone loss (peri-implantitis) and ultimately implant loss. With the continued use of dental implants, it is projected that the incidence of implant related complications is expected to rise. It is important to understand treatment options available for the management of long term implant complications. A number of strategies have been proposed, however, no superior treatment has been identified to-date.

Aims: This systematic review aims to systematically appraise available literature to evaluate the effectiveness of treatment for peri-implantitis in patients with functional osseointegrated dental implants.

Methods: Highly sensitive search strategies were developed for an electronic database search to maximise the retrieval of relevant records. Search strategies included a combination of search terms and Boolean operators. Hand-searching of relevant journals was also performed. Titles and abstracts derived from the systematic search were independently screened by a single reviewer (author). All duplicates were removed. The articles were subjected to clear inclusion and exclusion criteria.

Selection criteria: Randomised controlled trials designed to compare various treatment modalities for the treatment of peri-implantitis.

Results: The systematic search resulted in 476 titles. After limits were applied this resulted in 368 articles. 323 articles were excluded following evaluation of the title and abstract with 45 articles eligible for inclusion. After application of eligibility criteria, 14 parallel design comparative randomised controlled trials were considered for review. Nine described non- surgical interventions, whilst five described surgical interventions. Screening of eligible studies, assessment of methodological quality and data extraction were conducted by the author. Some study authors were contacted for missing information.

The professional management of peri-implantitis- a systematic review. 2 Data analysis: Qualitative and quantitative data extraction was carried out. Results were presented using forrest plots using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals (CI). No meta-analysis was carried out due to heterogeneity across included studies.

Conclusions: The findings of this systematic review revealed positive outcomes have been documented over short-term follow-up periods for some treatment modalities, however, long-term outcomes are not known. There is currently a lack of reliable evidence to suggest a superior intervention for the treatment of peri-implantitis. A combination of small sample sizes and short follow-up periods gave rise to a high degree of risk of bias across the included studies.

The professional management of peri-implantitis- a systematic review. 3 Dedication and Acknowledgements

My dissertation is dedicated to the memory of my grandfather who was always so proud of my achievements.

Thank you to my husband and my wonderful family. Their support and understanding over the duration of this MSc has been invaluable.

I would like to thank my mentor, Dr Ben Kemsley, for the support and advice provided during this project and corresponding authors that provided additional data when requested. Thank you to Dr Sam Leary at the University of Bristol, who provided consultation on any statistical matters.

The professional management of peri-implantitis- a systematic review. 4 Author’s declaration

I declare that the work in this dissertation was carried out in accordance with the requirements of the University’s Regulations and Code of Practice for Taught Programmes and that it has not been submitted for any other academic award. Except where indicated by specific reference in the text, this work is my own work. Work done in collaboration with, or with the assistance of others, is indicated as such. I have identified all material in this dissertation which is not my own work through appropriate referencing and acknowledgement. Where I have quoted or otherwise incorporated material which is the work of others, I have included the source in the references. Any views expressed in the dissertation, other than referenced material, are those of the author.

SIGNED:

DATE:

The professional management of peri-implantitis- a systematic review. 5 Table of contents

Contents Page Abstract 2 Dedication and Acknowledgments 4 Author’s declaration 5 Table of contents 6 List of figures 9 List of tables 10 List of abbreviations 12 Chapter 1- Introduction- plain language summary 14 Chapter 2- Literature review 17 2.1 History of implants 17 2.2 Biology of osseointegration 17 2.3 Implant success, survival, failure 19 2.4 Criteria of implant success. 20 2.5 Peri-implant diseases 22 2.5.1 Peri-implant mucositis 24 2.6 Pathogenesis of peri-implantitis 24 2.7 Aetiology of peri-implantitis 25 2.8 Epidemiology of peri-implantitis 29 2.9 Diagnosis of peri-implantitis 30 2.10 Peri-implantitis versus periodontitis 34 2.11 Bacteria 35 2.12 Prevention 35 2.13 Available treatments 36 2.14 Peri-implant mucositis 37 2.14.1 Mechanical non-surgical debridement 37 2.14.2 Adjunctive chemotherapeutics 38 2.15 Peri-implantitis 38 2.15.1 Non-surgical treatment for peri-implantitis 39 2.15.2 Adjunctive therapy to non-surgical treatment for peri-implantitis 39 2.15.3 Local antibiotics adjunctive to non-surgical debridement 40 2.15.4 Adjunctive systemic antibiotics 41

The professional management of peri-implantitis- a systematic review. 6 2.15.5 Surgical treatment for peri-implantitis 41 2.15.6 Closed surgical debridement versus open surgical debridement 41 2.15.7 Adjunctive treatment to surgical treatment of peri-implantitis 42 2.15.8 Adjunctive Systemic antibiotics 43 2.15.9 Regenerative surgical therapy 43 2.15.10 Ressective procedures: Apically repositioned flap with implantoplasty 45 2.16 Systemic antibiotics 45 2.17 Non-surgical versus surgical interventions 45 2.18 Conclusions and implications for future research 46 2.19 Methodology 47 2.20 Aims 47 2.21 Objectives 47 Chapter 3- Methods 48 3.1 Search methods 48 3.2 Review question 48 3.3 Search strategy 50 3.3.1 Searches 50 3.3.2 Selection 53 3.3.3 Inclusion criteria 53 3.3.4 Exclusion criteria 54 3.4 Data extraction 54 3.4.1 Unclear or missing information 54 3.4.2 Risk of bias/quality assessment 54 3.5 Statistical analysis 55 3.5.1 Meta-analysis 55 Chapter 4- Results 56 4.1 Excluded studies 56 4.2 Included studies 58 4.3 Presentation of study information 62 4.4 Description of studies 67 4.4.1 Description of studies- characteristics of study design 67 4.4.2 Description of studies- disease definition 67 4.4.3 Description of studies – inclusion criteria 69 4.4.4 Description of studies – exclusion criteria 69

The professional management of peri-implantitis- a systematic review. 7 4.4.5 Description of studies – interventions 78 4.4.6 Description of studies – outcome measures 79 4.4.7 Description of studies – follow up 79 4.4.8 Description of studies – sample size 80 4.4.9 Description of studies – Pre-treatment and maintenance 80 4.5 Quality assessment and risk of bias 82 4.6 Comparison of non-surgical interventions 85 4.7 Comparison of surgical interventions 87 4.8 Quantitative study results 91 4.9 Statistical analysis of data 101 4.9.1 Analysis 1 101 4.9.2 Analysis 2 101 4.9.3 Analysis 3 101 4.9.4 Analysis 4 102 4.9.5 Analysis 5 102 4.9.6 Analysis 6 102 4.9.7 Analysis 7 103 4.9.8 Analysis 8 103 4.9.9 Analysis 9 104 4.9.10 Analysis 10: 104 4.9.11 Analysis 11 105 Chapter 5- Discussion 106 5.1 Summary of findings 107 5.1.1 Summary of findings - Non-surgical treatment 107 5.1.2 Summary of findings - Surgical treatment 111 5.2 Summary 115 5.3 Quantitative analysis 115 5.4 Qualitative analysis 116 5.5 Critical appraisal of evidence 116 5.6 Recommendations for clinical practice 121 5.7 Recommendations for future research 121 5.8 Limitations of current review 122 Chapter 6: Conclusion 123 6.1 Algorithm 1: Maintenance of peri-implantitis 125

The professional management of peri-implantitis- a systematic review. 8 6.2 Algorithm 2: Summary of management of peri-implantitis 126 6.3 Algorithm 3: Non-surgical management of peri-implantitis 127 6.4 Algorithm 4: Surgical management of peri-implantitis 128 Appendices 129 Appendix 1: Protocol for systematic review 130 Appendix 2: Medline (OVID) database search strategy 135 Appendix 3: Medline in progress database search strategy 136 Appendix 4: Embase database search strategy 137 Appendix 5: Cochrane Oral Health Group Trials Register search strategy 138 Appendix 6: Diagnostic criteria for the diagnosis of peri-implantitis 139 Appendix 7: Risk of bias tables with authors judgment and support for 141 judgement. Appendix 8: References for included studies, 149 References 152

List of figures Page

Figure 1: Clinical photograph to show poor oral hygiene around a milled 23 implant bar. Figure 2: Clinical photograph to show peri-implantitis around a single implant 23 crown Figure 3: Clinical radiograph to show crestal bone loss around an implant. 24 Figure 4: Clinical photograph to show poor oral hygiene around implant 27 supported framework. Figure 5: Risk of bias graph 82 Figure 6: Risk of bias summary 82 Figure 7: Analysis 1 101 Figure 8: Analysis 2 101 Figure 9: Analysis 3 101 Figure 10: Analysis 4 102 Figure 11: Analysis 5 102 Figure 12: Analysis 6 102 Figure 13: Analysis 7 103 Figure 14: Analysis 8 103 Figure 15: Analysis 9 104 Figure 16: Analysis 10 104 Figure 17: Analysis 11 105

The professional management of peri-implantitis- a systematic review. 9 List of Tables Page Table 1: Summarises the biological process of osseointegration: 18 Table 2: Implant success criteria: 20 Table 3: Signs and symptoms of peri-implant diseases: 23 Table 4: Summary of causative and predisposing factors that have been 25 implicated in the aetiology of peri-implantitis with grading of the available evidence to support each. Table 5: Shows the reported prevalence of peri-implant diseases. From a 29 number of different studies identified in a literature search. Table 6: Table to summarise the diagnostic criteria for the diagnosis of peri- 32 implantitis reported across the literature. Table 7: Histologic comparison of periodontium and peri-implant supporting 34 apparatus Table 8: Outcomes for the adjunctive use of chemotherapeutics compared to 37 mechanical debridement. Table 9: PICO summary 49 Table 10: Hand searched journals with publisher information and impact factor. 52 Table 11: Excluded articles, comments and reasons for exclusion. 57 Table 12: Non-surgical comparative randomised controlled trials: 58 Table 13: Surgical comparative randomised controlled trials: 59 Table 14: Table to show the year of publication and respective number for the 60 included studies. Table 15: PRISMA flow chart of search strategy 61 Table 16: Study characteristics for non-surgical treatment of peri-implantitis 62 Table 17: Study characteristics for surgical treatment of peri-implantitis 64 Table 18: Diagnostic criteria for peri-implantitis used by the included studies. 68 Table 19: Summary of inclusion and exclusion criteria. 71 Table 20: Inclusion criteria 75 Table 21: Exclusion criteria of studies 77 Table 22: Table to show the intervention(s) evaluated by the included studies 78 Table 23: Pre-operative treatments and maintenance protocols 80 Table 24: Sponsorship/funding of included studies 81 Table 25: Study results for radiographic bone level 91 Table 26: Study results for pocket probing depths 93 Table 27: Study results for bleeding on probing 95 Table 28: Study results for suppuration on probing 97 Table 29: Study results for clinical attachment loss 98 Table 30: Study results for plaque index 99 Table 31: Presentation of summary of diagnostic criteria used across the 139

The professional management of peri-implantitis- a systematic review. 10

literature. Table 32: Risk of bias table: Caruac et al., 2015 141 Table 33: Risk of bias table: de Waal et al., 2012 141 Table 34: Risk of bias table: de Waal et al., 2014 142 Table 35: Risk of bias table: Esposito et al., 2013 142 Table 36: Risk of bias table: Javed et al., 2016 143 Table 37: Risk of bias table: Matechi et al., 2012 143 Table 38: Risk of bias table: Papadopoulos et al., 2015 144 Table 39: Risk of bias table: Persson et al., 2010 144 Table 40: Risk of bias table: Renvert et al., 2011 145 Table 41: Risk of bias table: Schwarz et al., 2007 145 Table 42: Risk of bias table: Schwarz et al., 2011 146 Table 43: Risk of bias table: Schwarz et al., 2012 146 Table 44: Risk of bias table: Schwarz et al., 2013 147 Table 45: Risk of bias table: Wohlfhart et al., 2012 148

The professional management of peri-implantitis- a systematic review. 11 List of abbreviations

BOP Bleeding on Probing aPDT Adjunct antimicrobial photodynamic therapy CAL Clinical Attachment Loss CHSSS Cochrane High Sensitive Search Strategy CHX Chlorhexidine CM Collagen Membrane

CO2 laser Carbon Dioxide Laser CPC Cetylpyridinium chloride DD Debridement decontamination EDTA Ethyldiaminetetracetic acid EMD Enamel matrix derivative ER-YAG laser Erbium-doped Yttrium Aluminium Garnet laser FMPS Full Mouth Plaque Score Gy Grays HP Hydrogen Peroxide IL-1 Inter leukin 1 ISD Implant surface debridement Ki-67 cellular marker for proliferation LA Local Antibiotics MeSH Medical Subject Heading MMP matrix-metalloproteinases NHA Nanocrystalline Hydroxyapatite NPSP Non- periodontitis susceptible patients NST Non-surgical treatment OF Open Flap PDGF Platelet-derived growth factor PI Plaque Index PICO Participants, Interventions, Comparisons, Outcomes PIPD Peri-implant Probing Depth PPD Peri-implant Pocket Depth PTG Porous titanium granules RBL Radiographic Bone Loss RCT Randomised Controlled Trial

The professional management of peri-implantitis- a systematic review. 12 RFA Resonance Frequency Analysis SAB Systemic Antibiotics SUP Suppuration TPS Titanium plasma spray VEGF Vascular endothelial growth factor

The professional management of peri-implantitis- a systematic review. 13 Chapter One- Introduction/plain language summary

Dental implants have revolutionised oral rehabilitation and prosthetic dentistry. High rates of implant survival have led implant-retained restorations to become a popular treatment option among both dentists and patients. With the increasing use of dental implants as a treatment modality the incidence of associated complications is expected to rise. Dental care professionals have a responsibility to understand the diagnosis and treatment options available for the management of long term implant complications: biological and mechanical, whether they are involved in placing or restoring implants or not.

The maintenance of healthy peri-implant tissues is a key predictor in their long-term success. There is a clear link between bacterial plaque accumulation and peri-implant disease.

In 2018, a new classification for peri‐implant conditions was proposed by the proceedings of the World Workshop on the Classification of Periodontal and Peri‐implant Diseases and Conditions (Berglundh et al., 2018). The classification describes the peri-implant tissues from a state of health to disease.

Peri-implant health: “Clinically, peri‐implant health is characterised by an absence of visual signs of inflammation and bleeding on probing. Peri‐implant health can exist around implants with normal or reduced bone support” (Berglundh et al., 2018).

Peri-implant mucositis: “Characterised by bleeding on probing and visual signs of inflammation. Peri‐implant mucositis can be reversed with measures aimed at eliminating the plaque” (Berglundh et al., 2018).

Peri-implantitis: “A plaque‐associated pathologic condition occurring in the tissue around dental implants, characterised by inflammation in the peri‐implant mucosa and subsequent progressive loss of supporting bone” (Berglundh et al., 2018).

Distinct differences in peri-implantitis incidence and prevalence have been reported by a number of authors with the true value likely to be under-reported. The prevalence of peri-

The professional management of peri-implantitis- a systematic review. 14 implantitis is likely to vary depending on the diagnostic criteria, as well as the number of smokers and the maintenance regime of the subjects within the cohort. A systematic review reported peri-implantitis incidence to be 22% within a range of 11% to 47% of subjects (Mombelli et al., 2012).

Clinical signs indicating the presence of peri-implant inflammation include bleeding on probing and/or suppuration. Peri-implantitis is associated with increased probing depths and radiographic bone loss beyond bony re- modelling. Implants should be examined regularly with routine monitoring and maintenance of peri-implant tissues. It is known from the evidence-base that un-treated peri-implantitis will lead to progressive loss of supporting bone (Albrekson et al., 1994).

Risk factors for peri-implant disease have been identified: including poor oral hygiene, a history of periodontitis, diabetes and smoking. Bacterial colonisation occurs almost immediately following implant placement. If peri-implant disease develops, a dominance of gram-negative anaerobic bacteria is seen. It is important to promote a supportive maintenance regime to prevent bacterial plaque accumulation in order to maintain peri- implant health. Evidence from a Cochrane review suggests peri-implant mucositis can be successfully treated with effective non- surgical therapy (Esposito et al., 2012).

Various protocols for the treatment of peri-implantitis have been proposed, including non- surgical mechanical debridement, the use of antiseptics, local and systemic antibiotics, as well as surgical and regenerative procedures. Despite a wealth of published literature, the evidence-base has not yet determined a superior treatment modality in the management of peri-implantitis.

Improved outcomes have been demonstrated with some treatment modalities, however, many of these studies have short-term follow-up periods, thus, longevity of treatment success is unclear. Critical appraisal reveals many of the studies have a high risk of reporting bias with heterogeneity in disease definition and reported outcomes. It is important to note; a successful outcome does not necessarily mean complete resolution of disease perhaps only improvements in parameters being studied. Whilst recommendations have been proposed a ‘gold-standard’ protocol is yet to be determined. Several authors have highlighted a clear need for further research.

The professional management of peri-implantitis- a systematic review. 15 Across multiple treatment protocols there are common elements. These include a pre- treatment phase to establish excellent oral hygiene followed by the chosen treatment. Generally, this includes non-surgical or surgical mechanical debridement of the implant with or without adjunctive therapy followed by supportive maintenance. The ideal outcome for the treatment of peri-implantitis would be resolution of disease. Clinically this presents as an absence of suppuration or bleeding on probing, no further bone loss and the re- establishment and maintenance of healthy peri-implant tissues.

A number of systematic reviews have already addressed the topic of peri-implantitis management (Mahato, Wu and Wang, 2016; Ramanauskaite and Tervonen, 2016; Heitz-Mayfield and Mombelli, 2014; Muthukuru et al., 2012; Kotsovilis et al., 2008) including a Cochrane review (Esposito et al., 2008) with an update in 2012 (Esposito et al., 2012). Overall, the reviews concluded “there is no reliable evidence to suggest a superior intervention for the treatment of peri-implantitis”.

This systematic review aimed to assess and appraise existing literature to evaluate the effectiveness of available treatments for peri-implantitis to aid clinicians in their management of peri-implantitis.

The author of this review recognises peri-implant diseases affect a significant number of dental implants and patients. If sufficient evidence is available, clinical guidelines for the management of peri-implantitis will be proposed in line with current literature.

The professional management of peri-implantitis- a systematic review. 16 Chapter Two- Literature Review

2.1: The history of Implants

Professor Brånemark is considered the pioneer for titanium endosseous dental implants. He presented his research carried out over 10 years at Cambridge University showing that bone can grow intimately onto the surface of titanium implants, in a process known as osseointegration (Brånemark et al., 1977). This important serendipitous discovery paved the way for further development of titanium implants for dental application. Dental implants have become established as an important part of modern dental practice and are used to facilitate replacement of missing teeth, from single units to full mouth reconstructions.

2.2: The Biology of Osseointegration

Bone healing around implants is a dynamic process resulting from a cascade of osteogenic vascular and immunological events resulting in the establishment of direct contact between vital bone and implant surface. The process of osseointegration includes: inflammation, vascularisation, bone formation and bone remodelling (Table 1). During these phases, there is constant interaction between various cell types, growth factors and cytokines (Bosshardt, Chappuis and Buser, 2016; Kohal et al., 2004).

The professional management of peri-implantitis- a systematic review. 17 Table 1: Biological process of osseointegration

The professional management of peri-implantitis- a systematic review. 18 2.3: Implant success, survival and failure

Across the literature implant longevity is widely reported however different criteria are used which can make comparisons between individual studies difficult. Dental implants are generally defined by ‘success’, ‘survival’ or ‘failure’.

Implant success generally means an implant is present at the time of review and fulfils certain pre-established clinical criteria. “Implant success may range anywhere from health to disease” (Misch et al., 2008) thus it is not easily defined. There are currently no universally accepted criteria of success. It may be measured at implant level, peri-implant soft-tissue level, prosthodontic level or by patient centred outcomes (described in section 2.4). Success in implant dentistry should ideally evaluate long-term outcomes of an implant- prosthetic complex as a whole.

Implant survival is the most commonly reported measure of longevity (Needleman et al., 2012). Survival describes “if the implant is in the mouth or if it has been removed” (Bruggenkate et al., 1990). “The condition of the implant is not taken into consideration” (Misch et al., 2008). Proponents of this definition argue survival provides the clearest definition of success. In contrast, it may be argued that functioning implants with ongoing complications could be wrongly interpreted as successful as implants in function are subject to biological and mechanical complications (Derks et al., 2014). Survival alone does not suffice to represent the clinical efficiency of the implant-prosthetic complex as a whole. Dental implants have reported high rates of survival >10 years when used to support dental prostheses (Simonis et al., 2010).

Implant failure “describes a condition whereby the implant requires removal” (Misch et al., 2008). Failure is easier to determine than success or survival.

The professional management of peri-implantitis- a systematic review. 19 2.4: Implant Success Criteria

A variety of factors can affect long-term implant outcomes including: surgical site selection and technique, patient factors, implant- and prosthesis-design and loading protocol (Ferreira et al., 2015; Needleman et al., 2012; Albrektsson et al., 1986). Various implant success criteria are shown in Table 2. “Reported success rates have been shown to decrease when the number of criteria used increases” (Papaspyridakos et al., 2011).

Table 2: Implant Success Criteria

Implant level

No mobility: Mobility of an implant is a terminal clinical sign (Papaspyridakos et al., 2011; Buser et al., 1990; Albrektsson et al., 1986). Implant stability can be assessed using resonance frequency analysis (RFA) (Makary et al., 2012; Ersanli et al., 2005) or insertion torque (Degidi et al.,2010).

No pain or discomfort on lateral or vertical movements (Misch et al., 2008; Buser et al., 1990). Absence of continuous peri-implant radiolucency (Papaspyridakos et al., 2011; Albrektsson et al., 1986). Radiographic crestal bone loss (Kline et al., 2002; Adell et al., 1986). Mean bone loss < 0.2 mm per year after 1st year of loading (Albrektsson et al., 1986). No mechanical issues relating to fracture of implant substructure (Steinebrunner et al., 2008).

Peri-implant soft tissue level Absence of infection or inflammation i.e. suppuration, swelling, exudate, bleeding (Figuero et al., 2014; Misch et al., 2008; Mombelli and Lang, 1994; Buser et al., 1990; Smith and Zarb, 1989; Albrektsson et al., 1986). Probing depths/ pocket depth < 5 mm (Froum and Rosen, 2012; Heitz-Mayfield et al., 2011; Persson et al., 2011; Heitz-Mayfield, 2008; Renvert et al., 2008; Mombelli and Lang, 1994; Albrektsson et al., 1986). Optimum soft tissue around implant neck and body (Misch, 2008) Adequate zones of non-mobile keratinized tissues > 2 mm (Adibrad et al., 2009) Adequate width of attached gingivae (Adibrad et al., 2009)

The professional management of peri-implantitis- a systematic review. 20

Prosthetic level Function Correct anatomical and occlusal form (Chambrone et al., 2010; Conrad et al., 2008; Tonetti and Schmid, 1994). Restorability The position of the implant allows a functional restoration to be placed (Buser et al., 1990). Aesthetics Macro, micro and soft tissue-aesthetics (Papaspyridakos et al., 2011; Orr, 2005a; Orr, 2005b; Belser et al., 2004; Vermylen et al., 2003).

Patient level Function The ability to eat, speak and chew without disturbance or discomfort (Guckes et al., 1996; Locker, 1998; Pjetursson et al., 2005; Belser et al., 2009; Baracat et al., 2011) Absence of tenderness or pain under lateral and vertical forces following primary healing (Buser et al., 1990; Albrektsson et al., 1986). Absence of persisting paraesthesia or foreign body sensation (Papaspyridakos et al., 2011; Buser et al., 1990).

Positive score on the Oral health related quality of life index (Lam et al., 2013) Aesthetics Macro, micro and soft tissue-aesthetics (Orr, 2005a; Orr, 2005b; Belser et al., 2004).

The professional management of peri-implantitis- a systematic review. 21 2.5: Peri-implant disease

One of the most frequently documented dental implant complications is inflammation of the peri-implant tissues, which also represents a leading cause for implant failure. Peri-implant diseases have been classified as either ‘peri-implant mucositis’ or ‘peri-implantitis’. Signs and symptoms for each disease process are shown in Table 3.

In 2018, the World Workshop on the Classification of Periodontal and Peri‐implant Diseases and Conditions proposed a new classification scheme. The workshop was co‐sponsored by the American Academy of Periodontology (AAP) and the European Federation of Periodontology (EFP) and included expert participants from all over the world (Berglundh et al., 2018).

Peri-implant health: “Defined both clinically and histologically. Clinically, peri‐implant health is characterised by an absence of visual signs of inflammation and bleeding on probing. Peri‐implant health can exist around implants with normal or reduced bone support” (Berglundh et al., 2018).

Peri-implant mucositis: “Characterised by bleeding on probing and visual signs of inflammation. While there is strong evidence that peri‐implant mucositis is caused by plaque, there is very limited evidence for non‐plaque induced peri‐implant mucositis. Peri‐implant mucositis can be reversed with measures aimed at eliminating the plaque” (Berglundh et al., 2018).

Peri-implantitis: “A plaque‐associated pathologic condition occurring in the tissue around dental implants, characterised by inflammation in the peri‐implant mucosa and subsequent progressive loss of supporting bone” (Berglundh et al., 2018). Untreated peri-implantitis may lead to complete implant disintegration and implant failure (Canullo et al., 2015; Heitz- Mayfield, 2008; Esposito et al., 1999).

An absence of a universally accepted definition for the exact parameters of peri-implantitis has been identified in the literature (Tallarico et al., 2016; Heitz-Mayfield et al., 2014).

The professional management of peri-implantitis- a systematic review. 22 Table 3: Signs and symptoms of peri-implant diseases

Peri-implant mucositis Peri-implantitis

• Bleeding on probing • Bleeding on probing • Swelling • Swelling • Increased probing depths • Increased probing depths • Pain • Pain • Suppuration • Suppuration • Swelling of the peri-implant tissues • Swelling of the peri-implant • No radiographic bone loss tissues • Radiological evidence of crestal bone loss Disease outcome: reversible Disease outcome: irreversible

Figure 1: Clinical photograph to show poor oral hygiene around a milled implant bar.

Figure 2: Clinical photograph to show peri-implantitis around a single implant crown.

The professional management of peri-implantitis- a systematic review. 23

Figure 3: Radiograph to show radiographic crestal bone loss

Circumferential radiographic crestal bone loss to the fourth implant thread.

2.5.1 Peri-implant mucositis

Presentation: Peri-implant mucositis is a reversible disease that may present with signs and symptoms described in Table 3. Histologically it is characterised by inflammation lateral to the junctional epithelium with the presence of inflammatory infiltrate including plasma cells and lymphocytes. Inflammation is confined to the junctional epithelium and supracrestal connective tissue is spared (Berglundh et al., 2018).

Aetiology: There is strong evidence from both animal and human experimental studies that plaque is the primary aetiological factor for peri-implant mucositis. There is very limited evidence to prove any other aetiological cause (Berglundh et al., 2018). Smoking, diabetes, radiation therapy and immunosuppression may influence the host response to a bacterial challenge.

2.6 Pathogenesis of peri-implantitis

Peri-implantitis is a progressive and irreversible disease (Ramanauskaite et al., 2018). The immune system responds to bacterial infection by mobilising neutrophils, macrophages, T cells, and B cells, which then migrate into the lesion (Belibasakis, 2014). Degenerative changes progress apically into the underlying connective tissue resulting in the loss of alveolar bone (Lang et al., 2011).

The professional management of peri-implantitis- a systematic review. 24 2.7 Aetiology of peri-implantitis

Aetiological factors linked to the development of peri-implantitis have been evaluated with varying levels of supporting evidence (Table 4). Appraisal of available studies revealed significant variations in study design, methodology, outcome variables, follow-up periods and disease definitions. Studies were not always adjusted for confounding factors and a lack of meta-analysis means it is not possible to draw robust conclusions.

Further research is required to produce high powered, robust data, through prospective longitudinal studies with sufficient long term follow up.

Table 4: Summary of aetiological factors for peri-implantitis

Causitive and predisposing aetiological factors for peri-implant disease. Quality of the body of evidence

Host Susceptibility Periodontal disease susceptibility Strong Keratinised tissue Weak Genetic traits Insufficient Gender Insufficient Diabetes Insufficient Osteoporosis Insufficient Radiation therapy Insufficient Prosthetic Design Prosthesis design Inconclusive Implant Design Implant design Inconclusive Patient Factors Oral hygiene Strong Smoking Strong Periodontal disease and smoking combined Strong Host bone versus grafted bone Insufficient Iatrogenic Factors Excess cement Strong evidence

The professional management of peri-implantitis- a systematic review. 25 Host susceptibility

Periodontal susceptibility: There is an increasing body of evidence to demonstrate patients with a history of periodontitis are at an increased risk for peri-implant disease compared with non- periodontitis susceptible patients (NPSP) (Rasperini et al., 2014; Mombelli et al., 1987).

Diabetes: Lower implant survival rates have been reported in some studies with diabetic patients (Salvi et al., 2008; Moy et al., 2005). The strength of available evidence is weak.

Radiation therapy: Animal and human studies suggest an increased risk of early implant failure up to 12 times (Yerit et al., 2006) in irradiated bone compared with non-irradiated bone (Zheng et al., 2014). Increased failure rates have also been observed when the radiation dose exceeds 45Gy (Nooh, 2013). The quality of available evidence is reasonable.

Keratinised tissue: Current evidence, although weak, suggests keratinised tissue thickness around dental implants is a determining factor for peri-implant disease (Roos-Jansåker et al., 2006). Thin tissue seems more susceptible to marginal breakdown in the presence of inflammation (Brägger et al., 2010; Wilson, 2009; Heitz-Mayfield, 2008).

Osteoporosis: Current evidence is equivocal on the effect of osteoporosis on implant survival (Neukam and Fleming, 2006; Dao et al.,1994).

Genetic traits: There is weak evidence to support the role of genetics in the development of peri-implant disease (Casado et al., 2013). There is a possible association between IL-1 gene polymorphism and peri-implantitis (Heitz-Mayfield, 2008).

Gender: There is very weak evidence found in an isolated cross-sectional study (Ferreira et al., 2006) to support the role of gender as a risk indicator in the development of peri-implant mucositis. This study suggests males may be at a higher risk, however, this was a small powered study in Brazilian subjects.

The professional management of peri-implantitis- a systematic review. 26 Prosthetic design

Prosthesis design: Poor prosthesis design can contribute to poor plaque control leading to peri-implant inflammation (Brägger et al., 2010; Heitz-Mayfield, 2008; Karoussis et al., 2003).

Implant design

Implant design: Studies have indicated implants with very rough surfaces such as hydroxyapatite surfaces and those sprayed with titanium-plasma have a higher incidence of peri-implantitis compared to machined surfaces (Quirynen et al., 2007; Karoussis et al., 2004).

Patient factors

Oral hygiene: Patients with poor plaque control are at an increased risk of peri-implantitis (Lindhe and Meyle, 2008; Berglundh et al., 1992). The level of evidence to support the association between plaque and peri-implant disease is reasonable and has been shown in cross sectional and experimental studies.

Figure 4: Clinical photograph to show poor oral hygiene around an implant supported bar.

Cigarette smoking: A number of systematic reviews and meta analyses have shown cigarette smoking as a risk factor for peri-implant disease (Heitz-Mayfield and Mombelli, 2014; Hinode et al., 2006;). A meta-analysis estimated smoking increased the annual rate of bone loss by 0.16 mm/year (Clementini et al., 2014) whilst other studies have shown failure risk to be increased by a factor of 2.5 to 4.6 (Heitz-Mayfield and Huynh-Ba, 2009). Smoking may represent the main systemic risk factor for peri-implantitis.

The professional management of peri-implantitis- a systematic review. 27

Periodontal susceptibility and smoking: A history of treated periodontitis combined with smoking has been shown to increase the risk of implant failure and peri-implant bone loss (Levin et al., 2011; Heitz-Mayfield and Huynh-Ba, 2009).

Host bone versus grafted bone: There is no evidence to suggest an increased risk of peri- implantitis in grafted sites (Misch, 2008; Naert et al., 2002; Esposito et al., 1998)

Alcohol consumption: There is limited evidence excessive alcohol consumption (>10g daily) may result in increased risk for peri-implantitis (Galindo-Moreno et al., 2005).

Iatrogenic factors

Excess cement: Excess sub-gingival cement extruded between the abutment and implant shoulder has been shown to increase plaque accumulation with an increase in gram negative anaerobic bacteria leading to peri-implant inflammation and bone loss (Lang, Kiel and Anderhalden, 1983).

Other potential emerging factors

“The role of occlusal overload, titanium particles, bone compression necrosis, overheating, micro-motion, bio-corrosion as risk indicators remains to be determined” (Berglundh et al., 2018).

2.8 Epidemiology of peri-implantitis Currently available epidemiological data is limited and it has been suggested the true prevalence of peri-implantitis is still unknown and perhaps underreported (Lee et al., 2017). A consensus report identified the prevalence of peri-implantitis to be 28% - 56% of patients and 12-40% of implants (Lindhe et al., 2008).

Studies designed to determine the prevalence of peri-implant disease report a range of values (Table 5). This is likely due to study heterogeneity, different diagnostic definitions and different study selection criteria.

The professional management of peri-implantitis- a systematic review. 28

Table 5: Reported prevalence of peri-implant diseases.

Reference Study design Time in Peri-implant mucositis (%) Peri-implantitis (%) n = number of implants function (S = subjects; I = implants) (S = subjects; I = implants) (mean years) Dalago et al., 2016 Cross-sectional ? Not described 16.4 (S) n=916 Rokn et al., 2016 Cross-sectional 4.43 48.5 (S) 20 (S) n=478 40 (I) 8.8 implants Daubert et al., 2015 Cross-sectional 10.9 48 (S) 26 (S) 33 (I) 16 implants Derks and Tomasi, 2015 Systematic review with ? 43 (S) (range: 19- 65) 22 (range: 1 – 47) meta-analysis Schwarz et al., 2015 Cross-sectional 23 months 41.6 (S) 13.9 (S) n=512 median 35.6 (I) 7.6 implants Aguirre-Zorzano et al., Cross-sectional ? 24.7 (S) 15.1 (S) 2014 n=786 12.8 (I) 9.8 implants Koldsland et al., 2010 cross-sectional 8.4 39.4 (S) 47.1 (S) n=351 range 1-16 27.3 (I) 36.6 implants Roos-Jansaker et al., Cross-sectional/ Range 9-14 Not described 16 (S) 2006 n=999 6.6 implants Fransson et al., 2005 Cross-sectional 10.8 59.6 (S) 14.9 subjects n=3413 range 9-14

The professional management of peri-implantitis- a systematic review. 29

2.9 Diagnosis of peri-implantitis

Different diagnostic criteria have been proposed to aid diagnosis of peri-implant health and disease (Heitz-Mayfield, 2008). There does not appear to be a universally accepted classification or diagnostic criteria for peri-implantitis. “Diagnostic measures need to be sensitive enough to detect the early signs to prevent lasting damage” (Mombelli and Lang, 1998).

Current consensus indicates clinical changes in probing depth and the presence of bleeding on probing +/- suppuration must be evaluated to assess peri-implant tissues. Radiographs should be used to evaluate peri-implant bone loss (Serino et al., 2012; Heitz-Mayfield, 2008;).

Different thresholds for clinical and radiographic parameters have been reported across the literature (Table 6).

Probing: An increase in probing depth may be associated with loss of attachment and supporting bone (Heitz-Mayfield, 2008). Probing around implants using a light force of 0.25 N has been suggested (Heitz-Mayfield, 2008; Lang et al.,1994).

The reported threshold for probing depth varies according to the author (Table 6), however, a suggested value of > 5mm has been described by many (Berglundh et al., 2018; Heitz- Mayfield et al., 2011; Gotfredsen, 2009; Albrektsson et al., 1986).

Bleeding: The presence of BOP is a sign of soft-tissue inflammation and is considered a valuable parameter for diagnosing peri-implant disease (Heitz-Mayfield, 2008; Lang et al., 1994;). Bleeding on probing is frequently seen at implants without irreversible bone loss therefore should not be used in isolation for the detection of peri-implantitis (Mombelli et al., 2012; Adell et al., 1986).

Suppuration: May indicate the presence of an infection (Lang and Berglundh, 2011; Mombelli and Lang, 1998). It has also been suggested suppuration is not used in isolation but with other diagnostic factors (Ramanauskaite and Juodzbalys, 2016).

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Bone loss: Bone loss is considered the most important parameter to differentiate peri- implant mucositis and peri-implantitis (Heitz-Mayfield, 2008). Bone-loss thresholds again differ across the literature (Table 6).

Following placement and loading of an implant, bone remodelling occurs resulting in some loss of crestal bone height. Bone loss has been shown to vary between implant design and manufacture (Albrektsson, Buser and Sennerby, 2012; Ekelund et al., 2003; Albrektsson et al., 1986; Adell et al., 1981). Animal and human studies suggest the position of the implant- abutment interface is also determinant to the amount of bone loss (Moustafa Ali et al., 2018; Lee et al., 2014; Cochran et al., 2013; Broggini et al., 2006; Broggini et al., 2003; Hermann et al., 1997).

Conclusions from the sixth, seventh and eighth European workshops on periodontology suggest a diagnosis of peri-implantitis should be made when changes in the level of crestal bone occur compared to baseline data (Sanz and Chapple, 2012; Lindhe and Meyle, 2008). Where previous radiographs are not available, a threshold vertical distance of 2 mm from the expected marginal bone level (following remodelling post-placement) is recommended in the presence of peri-implant inflammation (Sanz and Chapple, 2012).

Microbial analysis: There is evidence to suggest levels of matrix-metalloproteinases (MMP) such as MMP-8, are increased in peri-implant lesions (Lang and Berglundh, 2011)

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Table 6: Summary of diagnostic criteria for the diagnosis of peri-implantitis

Reference BOP SUP PD (mm) Bone loss (mm)

Ata-Ali et al., 2015 ✅ ✅ Not defined Stage I: < 3 Stage II: > 3 but < 5 Stage III: ≥ 5 Stage IV: ≥ 50% of the implant length Canullo et al., 2015 ✅ ✅ 3-5 >3 Froum et al., 2015 ✅ ✅ >/=6 >/=2 Padial-Molina et al., 2014 ✅ ✅ > 6 ≥ 2

Cecchinato et al., 2012 ✅ ✅ >/=4 >0.5 Froum and Rosen, 2012 ✅ ✅ Early ≥ 4 <25% of implant length Moderate ≥ 6 25-50% of implant length Advanced ≥ 8 >50% of implant length

Lopez-Piriz et al., 2012 ✅ ✅ Not defined >/=3 Marrone et al., 2012 ✅ ✅ >4 >/=2 Mir-Mari et al., 2012 ✅ ✅ >5 >/= 2 threads Ravald et al., 2012 ✅ ✅ >4 >/2 Charalampakis et al., 2011 ✅ ✅ >/=5 >/=1.8 Dvorak et al., 2011 ✅ ✅ >5 Bone loss beyond expected remodelling. Persson et al., 2011 ✅ ✅ >/=5 3 Roccuzzo et al., 2011 ✅ ✅ >4 >/=2 Stokerat et al., 2011 ✅ ✅ >5 >/=3 Schwarz et al., 2010 ✅ ✅ >6 >3 Wahlström et al., 2010 ✅ ✅ Not defined >/=2

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Zetterqvist et al., 2010 ✅ ✅ >5 >5

Gotfredsen, 2009 ✅ ✅ >/=5 >/=2 Heitz-Mayfield, 2008 ✅ ✅ > 5 Circumferential bone loss.

Lindhe and Meyle, 2008 ✅ ✅ Deepened pockets Always accompanied by loss of supporting marginal bone. No stated value.

Misch et al., 2008 ✅ ✅ >7 > 4 < 1/2 implant body

Renvert et al., 2008 ✅ ✅ >/=5 >3 Salvi et al., 2007 ✅ ✅ ≥ 5 ≥ 2 Persson et al., 2006 ✅ ✅ ≥ 5 ≥ 2 Renvert et al., 2006 ✅ ✅ >/=5 >3

*BOP- Bleeding on Probing, SUP- Suppuration, PD- Probing Depth.

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2.10 Peri-implantitis versus periodontitis

Aetiological risk factors for peri-implantitis and periodontitis are similar. Many treatments for peri-implantitis have been proposed analogous to the treatment of periodontitis. It has been suggested faster disease progression around implants is due to physiological differences in connective tissue morphology (Lang and Berglund, 2011). In Table 7, the histology of periodontium and peri- implant supporting tissues are compared.

Table 7: Histologic comparison of periodontium and peri-implant supporting tissues (Berglundh et al., 1991; Lindhe and Berglundh, 1998).

Peri-implant mucosa Physiological periodontium Anchoring system of root cementum, Direct bone-to-implant contact. No alveolar bone and desmodontic fibres. periodontal ligament or cementum. Tooth not in direct contact with the bone.

More sub epithelial fibroblasts and vessels. More sub epithelial collagen fibres and less Increased vascularization. Low collagen to fibroblasts/vessels. Reduced vascularization. fibroblast ratio. High collagen to fibroblast ratio.

Parallel orientation of collagen fibres in Dento-gingival, dento-periosteal, circular relation to implant surface- fibres not inserted and trans-septal fibre orientation. directly into implant. Junctional epithelium originates from oral Junctional epithelium originated from epithelium: basal lamina and hemi reduced enamel epithelium. Basal lamina desmosomes. Poorly adherent, poor and hemi desmosomes. Complete regenerative capacity. attachment to enamel.

The professional management of peri-implantitis- a systematic review. 34

Differences in the host response at teeth versus implant sites have been reported (Heitz- Mayfield and Lang, 2000). Peri-implantitis lesions show increased formation of inflammatory infiltrate, nitric oxide, vascular endothelial growth factor (VEGF), lymphocytes, leukocytes and Ki-67 (Degidi et al., 2011).

It is important to note many of the studies designed to experimentally induce peri- implantitis and periodontitis use animal ligature models. This may not be entirely similar to naturally occurring inflammation.

2.11 Bacteria

Peri-implantitis is a poly-microbial anaerobic infection (Charalampakis et al., 2011). The microbiota associated with healthy peri-implant tissues are dominated by gram-positive facultative cocci and rods (Mombelli and Décaillet, 2011). The microbiota associated with peri-implantitis lesions are not typical for periodontopathic microbiota. Sites are typically dominated by high counts of gram-negative anaerobic bacteria (Botero et al., 2005; Lekholm et al., 1986), such as: Prevotella intermedia, Prevotella nigrescens, Streptococcus constellatus, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia (Rams, Degener and van Winkelhoff, 2013). A number of studies have also reported an association between Staphylococcus aureus and peri-implantitis lesions. Staphylococcus aureus has been shown to have a high affinity to titanium (Salvi et al., 2008).

2.12: Prevention

“A cause-effect relationship has been demonstrated between dental plaque and peri- implant diseases” (Mombelli et al., 2007). There is a lack of evidence with respect to optimal self-performed oral hygiene around dental implants. At present, home care recommendations are based on knowledge available for cleaning natural teeth.

A Cochrane review showed a 21% reduction in plaque with powered toothbrushes around teeth when assessed after three months of use compared with manual tooth brushing

The professional management of peri-implantitis- a systematic review. 35

(Yaacob et al., 2014). Powered brushes have been reported as safe and comfortable for use in subjects with implant supported restorations (Vandekerckhove et al., 2004).

In two randomised controlled studies specifically designed to evaluate implants, no overall significant differences were reported between manual and sonic powered toothbrushes (Noyun et al., 2017; Lee et al., 2015).

Preventing the progression of reversible peri-implant mucositis into irreversible peri- implantitis is fundamental. The literature is clear that if left unmanaged peri-implant mucositis can develop into peri-implantitis (Schwarz et al., 2015). In a retrospective study, Costa et al. (2011) concluded “the absence of preventive maintenance in individuals with pre-existing peri-implant mucositis was associated with a high incidence of peri- implantitis”. Diligent monitoring and supportive maintenance is required for every patient (Heitz-Mayfield et al., 2016). High quality randomised controlled clinical trials are required to inform the development of an evidence based preventive protocol.

2.13 Available treatments

Cochrane reviews have concluded “there is no reliable evidence to suggest a superior intervention for the treatment of peri-implant mucositis or peri-implantitis.” (Esposito et al., 2012). Long-term randomised controlled studies are warranted.

Many interventions investigated in individual studies have demonstrated positive results recorded on clinical parameters being studied, however, positive outcomes do not necessarily lead to resolution of disease. Critical appraisal revealed many of the studies had short-term follow-ups and a high risk of reporting bias with heterogeneity in disease definition and reported outcomes.

The professional management of peri-implantitis- a systematic review. 36

2.14 Peri-implant mucositis

Fundamental to the elimination of peri-implant mucositis is good oral hygiene with effective plaque removal and disruption of biofilm. Mechanical plaque control can be effective with or without adjunctive chemical plaque control. Clinical parameters should be evaluated at regular intervals to monitor and prevent disease progression (Heitz-Mayfield and Mombelli, 2014).

2.14.1 Mechanical non-surgical debridement A number of randomised controlled trials have demonstrated mechanical non-surgical therapy effective in the treatment of peri-mucositis (Heitz-Mayfield et al., 2011; Renvert et al., 2008). The literature describes positive outcomes for reduction in bleeding and pocket depth reduction with the use of curettes (resin, carbon or titanium), ultrasonic instrumentation, rubber cup/polishing brushes (Schwartz et al., 2006) and air abrasion (Ji et al., 2013; Renvert et al., 2011).

2.14.2 Adjunctive chemotherapeutics Long-term data to support the adjunctive use of chemotherapeutic treatments is limited. Table 8 shows reported outcomes for mechanical debridement with the adjunctive use of chemotherapeutics compared to mechanical debridement alone.

Table 8: Outcomes for the adjunctive use of chemotherapeutics compared to mechanical debridement alone.

Chlorhexidine Minimal or no additional benefit with chlorohexidine gel or mouthwash (Heitz-Mayfield et al., 2011; Thöne-Mühling et al., 2010; Trejo et al., 2006; Felo et al., 1997). Minocycline Minimal or no additional benefit (Bassetti et al., 2013; Schär et al., 2012). Chloramine Minimal or no additional benefit (Roos-Jansåker et al., 2017; 2015). Antiseptic mouth Positive benefit (Cianco et al., 1995). The strength of the evidence rinse (Listerine) is weak; the study is based on a sample size of 20 subjects with a short duration (3 month) follow up.

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Phosphoric acid Microbial reduction using 35% phosphoric acid gel (Sahrmann et al., 2011; Strooker et al., 1998). Weak evidence with a small sample size and short follow-up, studies also showed a high risk of bias. Probiotic supplements No additional benefit (Hallström et al., 2015).

Systemic antibiotics No additional benefit (Hallström et al., 2012).

2.15 Peri-implantitis

A number of treatment strategies for peri-implantitis have been proposed. In general, therapies are based on treatments used for teeth with periodontitis. A Cochrane systematic review completed in 2008 and updated in 2012, included nine randomised controlled trials and concluded “there is no evidence to suggest a superior protocol for the management of peri-implantitis” (Esposito et al., 2012; Esposito et al., 2008;). Further systematic reviews have drawn similar conclusions (Ramanauskaite and Tervonen, 2016; Mahato, Wu and Wang, 2016; Heitz-Mayfield and Mombelli, 2014; Muthukuru et al., 2012; Kotsovilis et al., 2008).

Proposed treatments have been both non-surgical and surgical in approach with or without adjunctive therapy. Across available literature data is limited. There is significant variation across studies with regards to methodology, disease definition, outcome variables and follow-up periods. Many studies have small sample sizes with short duration follow-ups. Varying levels of bias across the studies with heterogeneity in reported data make meta- analysis difficult. Randomised controlled clinical trials with high power, longer follow-ups and more subjects are required.

The professional management of peri-implantitis- a systematic review. 38

2.15.1 Non-surgical treatment Limited data exists for non-surgical treatment of peri- implantitis. Of the available evidence, it has been suggested that little benefit can be expected (Schwarz et al., 2006; Hayek et al., 2005). Screw shaped implant designs and surface modifications can pose a challenge to ensure effective mechanical non-surgical therapy.

Non-metal scalers: In-vitro studies suggest that non-metal instruments do not allow complete biofilm removal during manual debridement (Augthun et al., 1998).

Metal scalers: In-vitro studies have shown metal instruments to be effective in biofilm removal at the implant surface. Metallic curettes are more effective in removing superficial material when compared to titanium curettes and ultrasonic tips covered with plastic inserts (Mengel et al., 1998).

Ultrasonic scaler: A split mouth design study compared mechanical debridement with the Vector system versus manual debridement with both interventions repeated after 3 months (Karring et al., 2005). No statistically significant differences were reported for the implants treated either by the ultrasonic device or manually between baseline, 3 or 6 months. This study is considered high risk of bias by the author of this review. The study had a very small sample size (11 subjects) with a short duration follow-up (6 months). The study concluded that debridement alone, is not sufficient for the decontamination of implant surfaces with peri-implantitis.

Other: A recently published study by Wohlfahrt et al. (2017), evaluated the effect on peri- implant mucosal inflammation with the use of a novel instrument made of chitosan in the non-surgical treatment of mild peri-implantitis across several clinical centres. The results were promising at 6 months with significant reductions in inflammatory clinical parameters. The major limitation of this study is that all subjects treated had bone loss of 1 – 2 mm.

2.15.2 Adjuncts to non-surgical treatment of peri-implantitis

Laser therapy: A number of studies are available for the adjunctive use of laser therapy using Er: YAG lasers, CO2 laser and Diode lasers. According to a literature review the Er: YAG has stronger documented evidence for beneficial adjunctive effects (Ashnagar et al., The professional management of peri-implantitis- a systematic review. 39

2014). It is unclear whether these effects can be maintained over time (Schwartz et al., 2005). Available evidence is based on data from studies with small sample sizes and short- term follow-up periods (< 6 months) with studies considered at high risk of bias by the author of this review. Positive treatment outcomes for laser therapy at least provide a foundation for future research with more research required to determine the long-term effects of laser therapy.

Antiseptic agents: A human in-vivo pilot study showed a significant bactericidal effect for adjunctive sodium hypochlorite, hydrogen peroxide, chlorhexidine, and Listerine against bacteria adhering to implant surfaces (Gosau et al., 2010).

Chlorhexidine: Machtei et al. (2012) demonstrated that frequent placement (every fourteen days) of chlorhexidine chips adjunctive to non-surgical debridement has been reported to lead to substantial improvements in clinical parameters (PD, CAL, BOP) at 6 months; the long-term effects of this treatment are undetermined.

2.15.3 Local antibiotics adjunctive to non-surgical debridement

There are very few randomised clinical trials evaluating the use of antibiotics in the treatment of peri-implantitis. Currently available information is insufficient to allow any firm recommendations for their use.

Metronidazole: In a parallel group design, 30 patients were enrolled and clinical outcomes for metronidazole gel versus ultrasonic debridement were compared at 12 weeks (Tang et al., 2002). This study produced no statistical differences between groups and is considered at high risk of bias by the author of this review.

Tetracycline: Mombelli et al. (2001) evaluated manual debridement with local delivery of tetracycline fibres in 25 patients with 30 implants. A positive effect on clinical (BOP, CAL, PPD) and microbiological parameters was seen at 6 months. Büchter et al. (2004) evaluated 8.5% doxycycline hyclate as an adjunct to manual debridement, reporting improvements in clinical parameters at 18 weeks. The risk of bias for this study is unclear, the follow up duration is short and the number of subjects is low. Complete resolution of disease was not achieved. Further long-term follow-up studies with more subjects are required.

The professional management of peri-implantitis- a systematic review. 40

Minocycline: In a series of randomised controlled trials positive improvements in clinical parameters (BOP, CAL, PPD) with the adjunctive use of locally administrated minocycline were seen at 6 months. Complete resolution of disease was not achieved (Renvert et al., 2004, 2006, 2008).

Persson et al. (2006) and Salvi et al. (2007) have shown the adjunctive use of either CHX gel or minocycline microspheres improve both clinical and microbiological parameters at 6 months. Further studies with larger sample sizes and longer-term follow-up periods are required.

2.15.4 Adjunctive systemic antibiotics The effects of adjunctive antibiotic therapy with non-surgical treatment of peri-implantitis remain debatable with very few studies available.

A retrospective study with 40 subjects comparing non-surgical treatment (NST) with systemic antibiotics (375 mg amoxicillin and 250 mg metronidazole) and NST alone found no difference between treatment outcomes for clinical and microbiological parameters at 3 months follow-up (Horst et al., 2015).

2.15.5 Surgical treatment for peri-implantitis Surgical treatment of peri-implantitis lesions has been suggested in cases with pockets > 5 mm and bone loss (Heitz-Mayfield et al., 2008). The aim of surgical treatment is to gain access to the exposed implant surface and the associated intra-bony defect for effective surface decontamination. No technique has been shown to be superior.

A number of human and animal studies exist; however, comparison of treatment outcomes is difficult due to differences in implant type, graft type, and evaluation protocols.

2.15.6 Closed- versus open-surgical debridement A number of individual studies have demonstrated positive outcomes for implant debridement following the raising of a flap and granulation tissue removal. The use of ultrasonic scalers (Schwarz et al., 2006), titanium or Teflon curettes and abrasive sodium

The professional management of peri-implantitis- a systematic review. 41

carbonate air-powder (Duarte et al., 2009) have been described. Animal studies have shown open-decontamination is more effective compared with closed- (Schou et al., 2004).

2.15.7 Adjuncts to surgical treatment of peri-implantitis

Currently available evidence is insufficient to draw reliable conclusions on a superior surgical treatment for peri-implantitis. A number of adjunctive treatments have been reported with varying success.

Laser decontamination: Deppe et al. (2001) reported small improvements in treatment outcomes with the adjunctive use of a laser with open flap debridement.

Hydrogen peroxide: In-vitro studies have shown that treatment of an exposed implant surface with 3% hydrogen peroxide is effective at reducing the number of bacteria at the implant surface (Bürgers et al., 2012; Zabtotsky et al., 1992). In a dog-model, treatment of the implant surface with 10% HP for 1 minute was shown to be an effective method of biofilm removal (Alhag et al., 2008).

Chlorhexidine: Multiple studies have shown CHX is effective in reducing the number of bacteria at implant surfaces (Hämmerle et al., 1995; Dennison et al., 1994; Lehmann et al., 1992). In-vivo, CHX has also been shown to contribute to re-osseointegration in dogs (Wetzel et al., 1999), and monkeys (Schou et al., 2003). In a randomised clinical trial to evaluate the effects of CHX on anaerobic bacterial load and putative periodontal pathogens, no significant results were found at 12 months (de Waal et al., 2012).

Citric acid: Citric acid has been suggested for decontamination of the implant surface. There is little agreement in the literature regarding concentration or duration of application.

Saline: Persson et al., (2004) and Persson et al., (1999) found no benefit in terms of bone regeneration or re-osseointegration when implant surfaces were treated with cotton pellets soaked in saline. Other studies have shown mechanical debridement and implant surface cleaning with saline soaked cotton pellets can lead to clinically stable results up to 24 months (Heitz-Mayfield et al., 2011; Schwarz et al., 2012, 2013).

The professional management of peri-implantitis- a systematic review. 42

Tetracycline: Tetracycline mixed with saline as a slurry has been suggested for implant surface cleaning. Evidence is available that tetracycline stimulates fibroblast growth in the affected area (Dennison et al., 1994; Zablotsky et al.,1992). Further case reports have shown positive clinical outcomes at 12 months when implant surfaces are treated with 50 mg/mL of tetracycline applied for 5 minutes after implantoplasty (Rozenfeld and Iacono, 2015; Park, 2011; Suh et al., 2003).

Air abrasion: Zablotsky et al. (1992) and Dennison et al. (1994) concluded air-abrasion, using bicarbonate particles mixed with saline solution is the best way to decontaminate hydroxyapatite coated implant surfaces compared with 40% citric acid or chlorhexidine 1%, which was not shown to be effective. Further studies have also shown air-abrasion to be effective (Mellado-Valero et al., 2013; Máximo et al., 2009). The strength of available evidence is limited with further research required.

2.15.8 Adjunctive systematic antibiotics

Currently available evidence is inconclusive on the benefit of adjunctive systemic antibiotics (Esposito et al., 2012; Subramani and Wismeijer, 2012). Most studies using a surgical approach prescribe a post-operative course of antibiotics. Azithromycin systemically administered for 5 days as an adjunct to open flap debridement did not provide 1-year clinical benefits in comparison to open flap debridement only (Hallström et al., 2017).

2.15.9 Regenerative surgical therapy

Peri-implant bony defects can be treated with surgical regenerative techniques (Lang et al., 2000). A limited number of randomised clinical trials have compared regenerative techniques. Of the available studies, short-term follow-ups (<12 months) are usually reported. Well-designed studies with long-term follow-up periods are necessary to verify if osseous fill is maintained long term.

A meta-analysis and systematic review reported no conclusions could be drawn regarding choice of biomaterials for peri-implant bone regeneration due to heterogeneity across studies (Daugela et al., 2016).

The professional management of peri-implantitis- a systematic review. 43

In a study by Schwarz (2006), 22 subjects were treated with either nanocrystalline hydroxyapatite (Ostim) or bovine bone (Bio-Oss) together with a resorbable collagen membrane (Bio-Gide) to treat peri-implant infrabony defects deeper than 3 mm. The results at 6 months demonstrated significant improvements in clinical parameters (BOP, CAL, PPD) for both groups. Further follow up at 2- and 4-years (Schwarz et al., 2009; Schwarz et al., 2008) demonstrated positive outcomes with results in favour of the Bio-Oss group. This study has relatively small sample size and unclear risk of bias.

Wiltfang et al. (2010) treated peri-implantitis defects with a mix of autologous bone and demineralized xenogenic bone graft including growth factors (Colloss E). Within the limits of the study (small sample size, short follow-up) the authors concluded the described procedure was effective in reducing peri-implant bone defects > 4 mm one year after treatment.

In a prospective study, Roccuzzo et al. (2011) evaluated regenerative surgical treatment of peri-implantitis lesions with bovine-derived xenograft (BioOss). 12-month follow-up demonstrated clinical and radiographic improvements. The authors reported complete bone defect fill is not predictable.

Roos-Jansåker et al. (2011; 2007) evaluated radiographic bone fill 12 months and 3 years following regenerative surgical treatment of peri-implantitis lesions (38 subjects) using a bone substitute (Algipore) with or without a membrane (Osseoquest). At 3 years pocket depth reduction was achieved and bone fill was a success. Statistical analysis failed to demonstrate changes between treatment groups, suggesting barrier membrane placement may not be necessary.

In combination with bone substitute materials, the use of enamel matrix derivative and platelet derived growth factor (PDGF) to enhance regenerative outcomes is encouraging but further research is required (Jepsen et al., 2016; Froum et al., 2015 and Wiltfang et al., 2010).

Porous titanium granules: A randomised clinical trial compared open flap debridement with or without defect reconstruction with porous titanium granules (PTG). The surfaces

The professional management of peri-implantitis- a systematic review. 44

were debrided with titanium curettes and decontaminated with EDTA 24% for 2 min followed by saline rinsing. Results at 1- and 7-years showed the treatment was not predictable. Treatment of defects with PTG requires further research (Wohlfahrt et al., 2017; 2012).

2.15.10 Resective surgical procedures

Implantoplasty refers to the modification of a rough implant surface using a drill to smoothen the surfaces exposed to the oral cavity. The objective is to reduce plaque adherence and facilitate implant maintenance (Suh et al., 2003).

Two randomised comparative clinical trials (Romeo et al., 2007, 2004) conducted over a three-year period, concluded that resective surgical procedures combined with implantoplasty could have a positive effect on clinical parameters and survival rates of rough-surfaced implants affected by peri-implantitis. These findings, in their limited state, are positive and should be used to inform further research.

2.16 Systemic antibiotics There are currently no clinical studies to demonstrate the effect of antibiotics as a monotherapy in the treatment of peri-implantitis. In all studies, systemic antibiotics are used as adjuncts to non-surgical or surgical procedures. It remains unclear if systemic or local antibiotics have a positive effect on treatment outcomes. To assess the effect of this treatment, randomised double-blind, placebo-controlled trials are required.

2.17 Surgical versus non-surgical interventions

A split mouth design in a dog model (Schwarz et al., 2006) designed to compare open surgical debridement with closed non-surgical debridement showed statistically significant improvements for all clinical parameters in both groups. Superior re-osseointegration was reported at 3 months in the open surgical approach.

The professional management of peri-implantitis- a systematic review. 45

2.18 Conclusions and implications for future research

Although there is no strong evidence to support one treatment modality over another, there is evidence to support the effectiveness of some currently available treatments. There is a lack of high-powered randomised controlled trials.

Across available studies primary outcomes are variable with short follow-up periods and inconsistent disease definitions. There is limited data on long-term treatment effects. Where short-term results are promising it may be that repeated intervention is required at varying intervals.

Further long-term randomised controlled studies are clearly required. Split mouth study designs with a placebo control would be of the highest power to account for confounding factors, however, this would not be ethical.

From the available body of evidence, first-line treatment for peri-implant disease should be non-surgical scaling with or without adjunctive therapy for the removal of plaque and elimination of the bacterial biofilm (Faggion and Schmitter, 2010). According to Renvert (2008) evidence suggests non-surgical therapy is ineffective for the treatment of peri- implantitis, however, should always be considered as a first line treatment.

If no improvement is recorded in clinical parameters (including BOP and PPD) following non-surgical debridement, surgical intervention may be considered. Surgical debridement with an open flap approach is considered superior to closed debridement. The adjunctive use of local or systematic antibiotics may also be considered.

Regenerative procedures using xenograft with or without a membrane have been shown to be effective and should be considered. Resective procedures such as implantoplasty may also be considered.

The professional management of peri-implantitis- a systematic review. 46

A number of questions remain unanswered

Q Is non-surgical therapy effective for the management of peri-implantitis? If so what is the superior treatment? Q What is the superior treatment modality for surgical management of peri-implantitis?

Q What is the treatment protocol for a step wise clinical approach to the management of peri-implantitis?

2.19: Methodology

A number of systematic reviews have already addressed the topic of peri-implantitis management (Ramanauskaite and Tervonen, 2016; Mahato, Wu and Wang, 2016; Heitz- Mayfield and Mombelli, 2014; Muthukuru et al., 2012; Kotsovilis et al., 2008). Including a Cochrane review published in 2008 and updated in 2012 (Esposito et al., 2012; 2008). No superior treatment has been determined for the management of peri-implantitis.

2.20 Aims

The primary aim of this review is to systematically appraise available literature to evaluate the effectiveness of treatments for peri-implantitis in patients with functional osseointegrated dental implants. The review will serve to assess whether literature currently available can provide sufficient data to inform clinicians how to manage peri-implantitis. If sufficient evidence is available, the secondary aim is to provide clinical guidelines for treatment.

2.21 Objectives

In order to fulfil the aims of this review the following objectives will be set:

• Appraise the available literature for study design quality and bias. • Analyse qualitative data extracted from available studies. • Analyse quantitative data extracted from available studies. • Describe the treatment of peri-implantitis

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Chapter Three- Methods

3.1: Search methods

Methods for this systematic review including search terms, Boolean operator algorithms, inclusion/exclusion criteria and limits were determined from initial scoping searches and a protocol was written (Appendix 1).

This review was performed independently by the author following PRISMA guidelines for identification, screening, eligibility, and inclusion (Moher et al., 2009).

3.2: Focus question

“To assess the effectiveness of currently available treatments for peri-implantitis”.

The focus question was developed according to the population, intervention, comparison, and outcome (PICO) study design.

Table 9 shows the PICO model used to help define the search strategy for the focus question. The concept of PICO was introduced by (Richardson et al., 1995) to help specify a clinical question.

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Table 9: PICO Summary

Population Patients diagnosed with peri-implantitis.

Intervention/exposure Treatment for peri-implantitis (non- surgical and surgical).

Comparison As there is no defined standard of care for peri-implantitis any treatment in a randomised controlled trial was included:

• Comparison of different non-surgical and surgical interventions. • Adjunctive treatments to non-surgical and surgical interventions.

Outcomes

Primary outcomes • Implant failure • Complications and side effects • Recurrence of peri-implantitis • Radiographic marginal bone levels on intraoral radiographs taken with a reproducible parallel technique

Secondary outcomes

• Bleeding on probing • Clinical attachment level change • Gingival margin recession • Peri-implant probing/ pocket depth

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3.3 Search strategy

3.3.1: Searches

The systematic search strategy was developed with guidance from the ‘Cochrane Handbook for Systematic Reviews of Interventions’ (Higgins and Green, 2008) and PRISMA guidelines (Liberati, 2009). The strategy involved searches though electronic databases as well as hand searches.

Highly sensitive search strategies were developed for each electronic database to maximise retrieval of relevant records. Search strategies included a combination of search terms and Boolean operators. Each search strategy was developed from the Cochrane high sensitive search strategy (CHSSS) for identifying randomised controlled trials on Medline and revised appropriately for each database.

Appendices 2-5 show the search strategies developed for each database. It demonstrates searched Keywords and Medical Subject Heading (MeSH) as well as the use of truncation and Boolean operators ‘AND’ and ‘OR’ to enhance each search.

Data was extracted from: • Central Medline via Ovid • Embase via Ovid • The Cochrane Central Register of Controlled Trials • Web of science

Medline search strategy

MEDLINE is the United States National Library of Medicine database. It contains more than 23 million citations from over 5,600 indexed, scholarly, and peer-reviewed journals with context from 1946 to date. MEDLINE was searched via the Ovid online platform. (peri-implant.Ovid.com). For search strategy see Appendix 2.

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Embase via Ovid search strategy

Embase contains over 30 million abstracts and indices from more than 8,500 published, peer-reviewed journals, as well as in-press publications and conferences. Embase was searched via the Ovid online platform (peri-implant.Ovid.com). For search strategy see Appendix 4.

The Cochrane Central Register of Controlled Trials search strategy

CENTRAL is the Cochrane Library database that provides a highly concentrated source of reports of randomised controlled trials. CENTRAL was searched via its online platform. (peri-implant.onlinelibrary.wiley.com/cochranelibrary/search). For search strategy see Appendix 5.

Web of Science search strategy

Web of Science is a citation database. Citation searching has the potential to identify unique studies not available in databases already used, and is considered a useful adjunct to database searching (Greenhalgh, 2005). Web of Science was searched via its online platform (peri-implant.webofknowledge.com). For search strategy see Appendix 5.

Hand searching Hand searching included several dental journals as well as the bibliographies of the identified randomised controlled trials selected for full-text review. Hand searching has been recommended for systematic reviewers searching in order to minimise bias (Vassar, Atakpo and Kash, 2016).

Hand searching of all references of full text articles was also performed (Table 10):

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Table 10: Hand searched journals with publisher information and impact factor.

Journal title Impact factor *2016 Publisher

Journal of Dental Research 4.744 Sage Publications Inc.

Clinical Oral Implants Research 3.624 Wiley-Blackwell

European Journal of Oral Implantology 3.567 Quintessence Publishing Co.

Journal of Clinical Periodontology 3.477 Wiley-Blackwell

American Academy of Journal of Periodontology 3.03 Periodontology Clinical Implant Dentistry and Related 2.939 Wiley-Blackwell Research The International Journal of Oral and 2.263 Quintessence Publishing Co. Maxillofacial Implants

The Journal of Prosthetic Dentistry 2.095 Mosby-Elsevier

International Journal of Oral and 1.918 Churchill Livingstone Maxillofacial Surgery Journal of Oral and Maxillofacial Peri-implant B Saunders Co- 1.916 Surgery Elsevier Inc. The International Journal of 1.386 Quintessence Publishing Co. Prosthodontics

Journal of Oral Implantology 1.283 Allen Press Inc.

British Journal of Oral and 1.218 Churchill Livingstone Maxillofacial Surgery International Journal of Periodontics 1.113 Quintessence Publishing Co. and Restorative Dentistry Lippincott Williams and Implant Dentistry 1.107 Wilkins

* Impact Factor correct for 2016. Sourced from Incites Journal Citation Reports: https://jcr.incites.thomsonreuters.com

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Unpublished studies

No unpublished studies were included in this review.

3.3.2: Selection of studies

Titles and abstracts derived from the systematic search were independently screened by a single reviewer (author). All duplicates were removed. The articles were subjected to clear inclusion and exclusion criteria.

Full texts of studies meeting inclusion criteria were reviewed for eligibility and data extraction. Studies rejected at this or subsequent stages were recorded (Table 11) and reasons for exclusion recorded.

3.3.3: Inclusion criteria

To be eligible for inclusion, the study must:

• Be a randomised controlled trial • Describe a clinical intervention designed for the treatment of a condition compatible with the definition of peri-implantitis according to the latest definition of the American Academy of Periodontology, 2013 (American Academy of Periodontology, 2013) and the consensus from the Eighth European Workshop (Sanz and Chapple, 2012). • Include at least 10 participants with a follow up of 6 months minimum. • Include adult patients with at least one dental osseointegrated implant in function. • Clinical and/or radiographic changes reported. • Published in the last 10 years January 2007-September 2017.

Randomised comparative studies may include:

• Non-surgical versus surgical interventions • Comparison of different non-surgical and surgical interventions • Adjunctive treatments to non-surgical and surgical interventions

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3.3.4: Exclusion criteria

• Case reports and case studies • Systematic reviews, meta-analysis and literature reviews • Animal studies • In vivo studies

3.4: Data extraction

Identified studies were appraised and data was extracted and organised into tables. (Tables 8-24).

The following data was extracted and recorded: Title, authors, year of publication, country of origin, study design, number of participants, demographic details of participants, disease definition, intervention(s), follow up duration, outcomes recorded, results.

A narrative synthesis/appraisal of included studies was prepared.

3.4.1: Unclear or missing information or data

If required, an attempt was made to contact corresponding authors for obtaining missing, unclear or unpublished data.

3.4.2: Risk of bias/quality assessment

Quality assessment and assessment of risk of bias was undertaken by the author as part of the data extraction process. The quality of each included article was assessed using the Cochrane quality assessment tool (Higgins and Green, 2008). This 2-part tool was used to assess bias across studies. The Cochrane quality assessment tool focuses on six specific domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and 'other issues'). The information recorded during this assessment was recorded in Appendices 26-39 using each included study was given an

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overall risk of bias (Higgins and Green, 2008). This information was presented in a risk of bias table (Figure 6) using Review Manager software (RevMan 5.3).

Each article was critically appraised according to the critical appraisal skills programme PRISMA 2009 checklist. Each study was appraised based on presentation of methodology, data collection and presentation of results. Each study was reviewed to see if a sample size calculation had been performed and check if definitions of exclusion/inclusion criteria were recorded. This information was presented in the results section in narrative form.

3.5: Statistical analysis

Statistical data from studies was presented on a Forest plot. For dichotomous outcomes, the estimate of the effect of an intervention was expressed as risk ratios (RR) and 95% confidence intervals (CIs). For continuous outcomes, mean differences and standard deviations were used. This enabled graphical interpretation of the available data. The statistical unit used in the presentation of data was taken at the patient level and not the implant level.

3.5.1: Meta-analysis

Meta-analysis was not possible due to heterogeneity of data in included studies. Included studies demonstrated distinct variation in study design, inclusion/exclusion criteria, treatment protocols and methods as described in presented tables, therefore descriptive analysis and appraisal of the data was performed. The quality of each study was assessed using the Critical Appraisal Skills Programme and PRISMA-2009 Checklist.

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Chapter Four- Results

The systematic search of electronic databases (appendices 2-5), hand searching of relevant journals and bibliographies of articles resulted in 476 titles:

• Number of articles identified through electronic data bases (n =472) • Number of articles identified through manual searches (n = 2) • Number of articles identified through bibliography searches (n = 2)

After limits were applied this resulted in 368 articles. Of these, 323 articles were excluded on the basis of the evaluation of the title and abstract, leaving 45 articles eligible for inclusion. After application of the eligibility criteria, a total of 14 articles were considered for review.

• Records after duplicates removed and limits applied (n =368) • Records screened (n =368) • Records excluded (n =323) • Number of articles eligible for inclusion (n=45) • Number of articles included in review (n=14)

4.1: Excluded studies

45 full text articles were obtained and reviewed. 31 did not meet eligibility criteria and were excluded. Table 11 shows excluded articles and reasons for exclusion.

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Table 11: Excluded articles

Reason for exclusion: Study:

Hentenaar et al., 2017 Romeo et al., 2016 Arisan et al., 2015 Hamzacebi, et al., 2015 Gomi et al., 2015 Sahm et al., 2015 Diagnostic criteria not met. Wohlfahrt et al., 2014 Bassetti et al., 2014 Bassetti et al., 2013 Schär et al., 2012 Romeo et al., 2007 Tang et al., 2002 Roos-Jansåker et al., 2015 Bombeccari et al., 2013 Levin et al., 2013 Follow up < 6 months De Angelis et al., 2012 Büchter et al., 2004 Strooker et al., 1998: Mussano et al., 2013 Schar et al., 2013 Sahm et al., 2011 Not possible to differentiate between those affected Persson et al., 2010 by peri-implantitis and those with peri-implant Renvert et al., 2009 mucositis. Renvert et al., 2008 Renvert et al., 2006 Schwarz et al., 2006 Diagnostic criteria not clear: Authors emailed no Karimi et al., 2016 reply.

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4.2: Included studies

Studies included in this review evaluated non-surgical and surgical management techniques for peri-implantitis (Tables 12 and 13).

Table 12: Non-surgical comparative randomised controlled trials: Esposito M; Grusovin MG; De Angelis N; Camurati A; Campailla M; Felice P. (2013). The adjunctive use of light-activated disinfection (LAD) with FotoSan is ineffective in the treatment of peri-implantitis: 1-year results from a multicentre pragmatic randomised controlled trial. European Journal of Oral Implantology. 6(2): pp109-19, Javed, F., Abduljabbar, T., Carranza, G., Gholamiazizi, E., Mazgaj, D., Kellesarian, S. and Vohra, F. (2016). Efficacy of peri-implant mechanical debridement with and without adjunct antimicrobial photodynamic therapy in the treatment of peri-implant diseases among cigarette smokers and non-smokers. Photodiagnosis and Photodynamic Therapy, 16, pp.85-89. Machtei, E., Frankenthal, S., Levi, G., Elimelech, R., Shoshani, E., Rosenfeld, O., Tagger- Green, N. and Shlomi, B. (2012). Treatment of peri-implantitis using multiple applications of chlorhexidine chips: a double-blind, randomized multi-centre clinical trial. Journal of Clinical Periodontology, 39(12), pp.1198-1205. Persson, G., Samuelsson, E., Lindahl, C. and Renvert, S. (2010). Mechanical non-surgical treatment of peri-implantitis: a single-blinded randomized longitudinal clinical study. II. Microbiological results. Journal of Clinical Periodontology, 37(6), pp.563-573. Renvert, S., Lindahl, C., Roos Jansåker, A. and Persson, G. (2010). Treatment of peri- implantitis using an Er: YAG laser or an air-abrasive device: a randomized clinical trial. Journal of Clinical Periodontology, 38(1), pp.65-73.

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Table 13: Surgical comparative randomised controlled trials: Carcuac, O., Derks, J., Charalampakis, G., Abrahamsson, I., Wennström, J. and Berglundh, T. (2015). Adjunctive Systemic and Local Antimicrobial Therapy in the Surgical Treatment of Peri-implantitis. Journal of Dental Research, 95(1), pp.50-57. de Waal, Y., Raghoebar, G., Huddleston Slater, J., Meijer, H., Winkel, E. and van Winkelhoff, A. (2012). Implant decontamination during surgical peri-implantitis treatment: a randomized, double-blind, placebo-controlled trial. Journal of Clinical Periodontology, 40(2), pp.186-195. de Waal, Y., Raghoebar, G., Meijer, H., Winkel, E. and van Winkelhoff, A. (2014). Implant decontamination 2% chlorhexidine during surgical peri-implantitis treatment: a randomized, double-blind, controlled trial. Clinical Oral Implants Research, 26(9), pp.1015-1023. Papadopoulos, C., Vouros, I., Menexes, G. and Konstantinidis, A. (2015). The utilization of a diode laser in the surgical treatment of peri-implantitis. A randomized clinical trial. Clinical Oral Investigations, 19(8), pp.1851-1860. Schwarz, F., Hegewald, A., John, G., Sahm, N. and Becker, J. (2013). Four-year follow-up of combined surgical therapy of advanced peri-implantitis evaluating two methods of surface decontamination. Journal of Clinical Periodontology, 40(10), pp.962-967. Schwarz, F., John, G., Mainusch, S., Sahm, N. and Becker, J. (2012). Combined surgical therapy of peri-implantitis evaluating two methods of surface debridement and decontamination. A two-year clinical follow up report. Journal of Clinical Periodontology, 39(8), pp.789-797. Schwarz, F., Sahm, N., Iglhaut, G. and Becker, J. (2011). Impact of the method of surface debridement and decontamination on the clinical outcome following combined surgical therapy of peri-implantitis: a randomized controlled clinical study. Journal of Clinical Periodontology, 38(3), pp.276-284. Schwarz, F., Sculean, A., Bieling, K., Ferrari, D., Rothamel, D. and Becker, J. (2007). Two- year clinical results following treatment of peri-implantitis lesions using a nanocrystalline hydroxyapatite or a natural bone mineral in combination with a collagen membrane. Journal of Clinical Periodontology, 35(1), pp.80-87. Wohlfahrt JC; Lyngstadaas SP; Ronold HJ; Saxegaard E; Ellingsen JE; Karlsson S; Aass AM. (2012. Porous titanium granules in the surgical treatment of peri-implant osseous defects: a randomized clinical trial. International Journal of Oral & Maxillofacial Implants. 27(2): pp401-10,

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Table 14: Included studies: Year of publication

Year Number of studies published 2017 0 2016 1 2015 2 2014 1 2013 2 2012 4 2011 1 2010 2 2009 0 2008 0 2007 1 2006 0 Total 14

After full-text article selection and reading, relevant information from each article was extracted. A diagram of the search strategy is shown in (Table 15).

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Table 15: PRISMA flow chart of search strategy

Number of studies

Number of articles identified through data base searching using key words 472

Identification Number of articles identified through manual searches 2

Number of articles identified 2 through bibliography searches

Records after duplicates removed 368

Records screened Screening 368

Records excluded 323

Full-text articles assessed for eligibility 45

Eligibility Full-text articles excluded, with reasons 31

Studies included in qualitative Inclusion synthesis 14

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4.3: Presentation of study information

Table 16: Characteristics of studies for non-surgical treatment of peri-implantitis

Sample size Definition of Intervention Intervention Follow up Outcome Reference number of peri-implantitis Group 1 Group 2 (Months) measures implants (n) Implant failures Non-surgically Surgically treated *primary treated for peri- for peri- outcome. implantitis and implantitis and Recurrence of BOP 50% of them were 50% of them were peri-implantitis Esposito et al., 80 SUP randomly randomly BL 2013 12 months n=80 BL ≥3 mm. allocated to allocated to PD

receive an receive an SUP additional LAD additional LAD Plaque scores treatment treatment Adverse (FotoSan) (FotoSan) complications

PD Test-group: full 84 smokers n=125 BOP >30% CAL mouth scaling and Control-group: implants SUP BL Javed et al., 2016 peri-implant MD full mouth scaling 84 non-smokers PPD ≥4 mm 6, 12 months BOP with adjunct and peri-implant n=124 implants BL ≥3 mm. aPDT; MD alone.

Machtei et al., 60 BOP Treatment with Treatment with PD 2012 35 females, 25 SUP matrix chips chlorhexidine 6 months CAL males PPD ≥6 mm

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age 27-77 yrs. 10mm at weeks 2, 4, 6, at weeks 2, 4, 6, (mean 59.18) BL ≥ 2 mm. 8, 12 and 18 8, 12 and 18 n=77 PD Plaque BOP BOP >30% 1. MD with 37 (*31 Adverse events Persson et al., SUP titanium curette. 2. MD with completed study) Checkerboard 2010 PPD ≥4 mm N=17 ultrasonic device. 6 DNA–DNA BL ≥2.5 mm. N=14 n=31 hybridization,

microbiological sampling

*PD/PPD- pocket depth/peri-implant probing depth; SUP- suppuration; BL/RBL-bone loss/radiographic bone loss; OF- open flap; CAL- clinical attachment level; BOP- bleeding on probing; PI-Plaque index; RCT-randomised controlled trial; SAB-systematic antibiotics; ISD- implant surface decontamination; FMPS- full mouth plaque score; DD- debridement/decontamination; EDTA- ethylenediaminetetraacetic acid; Er:YAG laser- erbium-doped yttrium aluminium garnet laser; CM- Collagen membrane; NHA- Nanocrystalline hydroxyapatite. MD- mechanical debridement; CHX- chlorhexidine.

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Table 17: Characteristics of studies for surgical treatment of peri-implantitis

Sample size/ Definition of Follow-up Outcome Reference: Number of peri- Intervention Group 1 Intervention Group 2 duration measures implants (n) implantitis (months) BOP group 1: SAB+ ISD SUP BOP group 3: no SAB ISD with an antiseptic agent PPD SUP with an antiseptic 100 (n = 27); BL Carcuac et al., 2015 PPD >6 mm agent (n = 24); 12 n=179 group 2: SAB + ISD Adverse BL >3 mm. group 4: no SAB ISD with saline (n = 25); effects with saline (n = 24).

Plaque BOP BOP Decontamination with SUP SUP a placebo-solution 30 0.12% CHX + 0.05% PPD de Waal et al., 2012 PPD >5 mm (without CHX/CPC, 12 N=79 CPC (test-group) BL BL ≥2 mm. placebo-group). *primary

outcome bacterial load. BOP* BOP Primary Test: decontamination 44 SUP Control: 0.12% CHX outcome with a 2% CHX de Waal et al., 2014 n=108 PPD ≥5 mm + 0.05% CPC 12 Plaque solution BL ≥2 mm. SUP

PPD RBL Papadopoulos et al., BOP Open flap plus diode PD *primary 19 Open flap debridement 6 2015 SUP laser outcome

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PPD ≥6 mm CAL BL ≥2 mm. BOP Plaque 22 patients. 8 Treatment of peri- Treatment of peri- men, 14 implantitis lesions Plaque BOP implantitis lesions a women. using a nanocrystalline BOP SUP natural bone mineral Schwarz et al., 2007 (mean age hydroxyapatite (NHA) PD PPD >6 mm in combination with a 24 54.4 12.5 in combination with a CAL * BL ≥3 mm. collagen membrane years) collagen membrane primary (NBM1CM). (NBM1CM). outcome

n=22 Flap surgery, Flap surgery, granulation tissue 32 (11 men granulation tissue removal, and and 21 BOP removal, and implantoplasty. women; SUP implantoplasty. Surface surface DD using mean age PPD >6 mm BOP Schwarz et al., 2011 DD using an Er: YAG plastic curets+cotton 6 60.8 10.9 BL >3 mm. Bone fill laser (ERL) device, pellets+sterile saline years) then augmented with (CPS). then

bone mineral and augmented with bone n=38 membrane. mineral and membrane. Flap surgery, Flap surgery, granulation tissue 32 (11 men granulation tissue removal, and and 21 BOP removal, and implantoplasty. women; SUP implantoplasty. Surface surface DD using BOP Schwarz et al., 2012 mean age PPD>5 mm DD using an Er: YAG 24 plastic curets+cotton CAL 60.8 ± 10.9 BL >3 mm. laser (ERL) device, pellets+sterile saline years, then augmented with (CPS) then augmented n=38 bone mineral and with bone mineral and membrane. membrane.

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Flap surgery, Flap surgery, granulation tissue 32: granulation tissue removal, and 11 men and BOP removal, and implantoplasty. 21 women; SUP implantoplasty. Surface surface DD using BOP Schwarz et al., 2013 mean age PPD >6 mm DD using an Er: YAG 48 plastic curets+cotton CAL 60.8 ± 10.9 BL >3 mm. laser (ERL) device, pellets sterile saline years then augmented with (CPS) then augmented n=38 bone mineral and with bone mineral and membrane. membrane. OF debridement and Adverse surface OF debridement and effects BOP decontamination with surface PD SUP titanium curettes and decontamination with BOP Wohlfahrt et al., 2012 32 PPD>5 mm 24% EDTA gel with 12 titanium curettes and Implant BL >3 mm. addition of Porous 24% EDTA gel stability titanium granules. (RFA)

BL

*PD/PPD- pocket depth/peri-implant probing depth; SUP- suppuration; BL/RBL-bone loss/radiographic bone loss; OF- open flap; CAL- clinical attachment level; BOP- bleeding on probing; PI-Plaque index; RCT-randomised controlled trial; SAB-systematic antibiotics; ISD- implant surface decontamination; FMPS- full mouth plaque score; DD- debridement/decontamination; EDTA- ethylenediaminetetraacetic acid; Er:YAG laser- erbium-doped yttrium aluminium garnet laser; CM- Collagen membrane; NHA- Nanocrystalline hydroxyapatite. MD- mechanical debridement; CHX- chlorhexidine; RFA-resonance frequency analysis.

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4.4: Description of studies.

4.4.1 Characteristics of study design

All studies included in the review were parallel group randomised controlled trials including adult subjects. All studies were carried out at universities or in specialist clinics and published between 2007 and 2016.

Of fourteen included trials:

1 was conducted in Sweden (Carcuac et al., 2015) 4 in Germany (Schwarz et al., 2007; Schwarz et al., 20011; Schwarz et al., 2012; Schwarz et al., 2013. 1 in Greece (Papadopoulos et al., 2015) 1 in Saudi Arabia (Javed et al., 2016) 2 in The Netherlands (de Waal et al., 2012; de Waal et al., 2014). 1 in Norway (Wohlfahrt., et al 2012)

4.4.2: Description of studies: Disease definition

Table 18 shows variation in diagnostic criteria used by included studies. Although definitions are heterogeneous all included studies used the presence of BOP as diagnostic criteria for peri-implantitis.

All studies but one (Esposito et al., 2013) included increased peri-implant probing depths and radiographic bone loss in the diagnostic criteria.

The threshold values for probing depths ranged from 4- to 6-mm, always above 4mm (as defined in inclusion criteria for this review). Minimum threshold values for bone loss ranged from 2- to 3-mm but were all above 2mm as defined by inclusion criteria.

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Table 18: Diagnostic criteria used by included studies

Author/ Reference BOP SUP PPD (mm) BL (mm) ✅ ✅ Renvert et al., 2011 ≥5 >3 ✅ ✅ Persson et al., 2010 ≥4 >2.5 ✅ ✅ Machtei et al., 2012. ≥6 <10 >2

✅ ✅ Javed et al., 2016. ≥4 >3 ✅ ✅ Esposito et al., 2013 ? >3

✅ ✅ de Waal et al., 2012 >5 >2 ✅ ✅ Papadopoulos et al., 2015 ≥6 >2

✅ ✅ Carcuac et al., 2015 >6 >3 ✅ ✅ Schwarz et al., 2013 >6 >3

✅ ✅ Schwarz et al., 2012 >5 >3 ✅ ✅ Wohlfahrt et al., 2012 >5 >3

✅ ✅ Schwarz et al., 2011 >6 >3 Schwarz et al., 2007 ✅ ✅ >6 >3

✅ ✅ ≥5 de Waal et al., 2014 ≥2

*BOP- Bleeding on probing; SUP- Suppuration; PPD- peri-implant pocket depth; BL- bone loss.

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4.4.3: Description of studies: Inclusion criteria of studies

The following were specified inclusion criteria described by included studies, refer to Table 20 for individual study inclusion criteria.

• Osseointegrated implant in function. • Implant in function for >2 years • Bone loss identified radiographically • Peri-implant probing depths varying from >/=4mm – 10mm. • Pus exudation and/or soft tissue swelling and/ or soft tissue redness • BOP • Suppuration • Presence of keratinized peri-implant mucosa. • Good level of oral hygiene (plaque index<1)

4.4.4: Description of studies: Exclusion criteria of studies

The following were specified exclusion criteria described by included studies, refer to Table 21 for individual study exclusion criteria.

• Evidence of occlusal overload • Implant mobility • Hollow cylinder implants • Smokers (smoker defined by more than 10 cigarettes/day) • Systemic disease that could influence the outcome of the therapy (i.e. diabetes, osteoporosis, and bisphosphonate medication). • Continuous use of non-steroidal anti-inflammatory drugs or drugs known to cause gingival overgrowth. • Signs of acute periodontitis. • Presence of overhangs or margins • Untreatable implants • Received systemic or topical antibiotics over the previous 3 months • Received systemic or topical antibiotics over the previous 6 months

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• Patients requiring antibiotic prophylaxis at intervention • Patients unable to commit to 5-year follow-up • History of allergy to CHX or regular use of it

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Table 19: Summary of inclusion and exclusion criteria described by studies:

Study Inclusion criteria Exclusion criteria Carcuac et al., 2015 Severe peri-implantitis in ≥1 implants Compromised general health PPD ≥6 mm in at least 1 aspect of the implant SAT during the past 6 months +BOP/SUP Allergy to penicillin RBL >3 mm). de Waal et al., 2012 >/=1 endosseous implant with clinical signs of peri- History of head/neck radiation implantitis and RBL (PIPD >/=5mm BL >/=2mm Pregnancy and lactation implant in function for >/=2 years Insulin dependent diabetes Antibiotics in last 3 months Mental or physical disorder preventing oral hygiene maintenance BL exceeding 2/3 of implant Implant mobility Previous surgical treatment of the lesion de Waal et al., 2014 >/=1 endosseous implant with clinical and History of head/neck radiation radiographic signs of peri-implantitis Pregnancy and lactation PIPD >/=5mm Insulin dependent diabetes BL >/=2mm Antibiotics in last 3 months Implant in function for >/=2 years Mental or physical disorder preventing oral hygiene maintenance RBL exceeding 2/3 of implant Implant mobility Previous surgical treatment of the lesion Esposito et al., 2013 > 3 mm of BL Mobile implants Pus exudation and/or soft tissue swelling and/ or soft No clear clinical signs of inflammation (pus exudate and/or tissue redness. soft tissue swelling and/or redness)

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Untreatable implants Medical conditions that had an absolute contraindication to subgingival debridement Received systemic or topical antibiotics over the previous 3 months Patients requiring antibiotic prophylaxis at intervention Patients unable to commit to 5-year follow-up

Javed et al., 2016 Smokers (individuals who reported to be smoking at Pregnant and/or lactating females, habitual alcohol users, least 1 cigarette daily since at least 1 year. patients with systemic diseases such as diabetes mellitus, Non-smokers (individuals who reported to have never acquired immune deficiency syndrome and renal disorders consumed any form of tobacco product); and patients who reported to have used antibiotics, BOP 30% sites corticosteroids and NSAIDs within the past 90 days PD>4mm Machtei et al., 2012 21 years or older (i) History of allergy to CHX or regular use of it (ii) PD of 6–10 mm in depth horizontal inter-implant distance <2 mm (if an adjacent BOP and radiographic evidence of bone loss. implant existed); (iii) Titanium Plasma-sprayed or Availability for the 6-month duration of the study. hydroxyapatite coated implants; (iv) systemic conditions that might affect inflammation and bleeding; (v) Any local irritation that could not be negotiated (i.e. orthodontic appliances; ill-fitted restorations; apical pathology); (vi) systemic antibiotic therapy or periodontal/mechanical/local delivery therapy within 6 weeks prior to study entry and throughout the study duration; (vii) continuous use of non- steroidal anti-inflammatory drugs or drugs known to cause gingival overgrowth; (viii) pregnancy or intention to become pregnant in the next 6 months. Papadopoulos et al., BOP 2015 SUP PPD ≥6 mm BL ≥2 mm.

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Persson et al., 2010 At least one dental implant with bone loss identified (I) poorly controlled diabetes mellitus (HbA1c>/=6.5), (II) on intra-oral radiographs >2.5 mm use of anti-inflammatory prescription medications, or PPD>/=4 mm antibiotics within the preceding 3 months, and (III) BOP+/SUP on probing using a 0.2 N probing force. identified bone loss >2.5 mm in comparison with findings from radiographs taken immediately following placement of the implant supra-structure. Renvert et al., 2011 At least 1 implant with BL >3mm on intra-oral Poorly controlled diabetes HbA1c>7.0 radiograph. The use of anti-inflammatory meds 3 months prior or PPD>/=5mm during study. BOP and/or SUP when assessed with a 0.2N probing Antibiotics 3 months prior force. Medications with known side effects on gingival growth. Subjects requiring prophylactic antibiotics.

Schwarz et al., 2007 At least one screw-type implant Hollow cylinder implants PD of >6 mm Smokers (smoker defined by more than 10 cigarettes/day). BL>3 mm as detected on radiographs Systemic disease that could influence the outcome of the no implant mobility therapy (i.e. diabetes, osteoporosis, and bisphosphonate no evidence of occlusal overload medication). Presence of keratinized peri-implant mucosa to Signs of acute periodontitis facilitate a repositioning of the mucoperiosteal flap at Presence of overhangs or margins the augmented areas Good level of oral hygiene (plaque index<1)

Schwarz et al., 2011 At least one screw-type titanium implant Hollow cylinder implants Class Ib Class Ic or Class Ie defect configuration Systemic diseases that could influence the outcome of the PD of >6 mm therapy [i.e. diabetes (HbA1c <7), osteoporosis, BL>3 mm bisphosphonate medication] Presence of at least 2 mm of keratinized peri-implant Presence of acute periodontitis mucosa to facilitate a re-positioning of the Presence of overhangs or margins mucoperiosteal flap at the augmented areas, Evidence of occlusal overload (i.e. occlusal contacts plaque index (PI) <1 revealed appropriate adjustment), Implant mobility

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Schwarz et al., 2012 At least one screw-type titanium implant Hollow cylinder implants Class Ib Class Ic or Class Ie defect configuration Systemic diseases that could influence the outcome of the PD of >6 mm therapy [i.e. diabetes (HbA1c <7), osteoporosis, BL>3 mm bisphosphonate medication] Presence of at least 2 mm of keratinized peri-implant Presence of acute periodontitis mucosa to facilitate a re-positioning of the Presence of overhangs or margins mucoperiosteal flap at the augmented areas, Evidence of occlusal overload (i.e. occlusal contacts Plaque index (PI) <1 revealed appropriate adjustment), Implant mobility

Schwarz et al., 2013 At least one screw-type titanium implant Hollow cylinder implants Class Ib Class Ic or Class Ie defect configuration Systemic diseases that could influence the outcome of the PD of >6 mm therapy [i.e. diabetes (HbA1c <7), osteoporosis, BL>3 mm bisphosphonate medication] Presence of at least 2 mm of keratinized peri-implant Presence of acute periodontitis mucosa to facilitate a re-positioning of the Presence of overhangs or margins mucoperiosteal flap at the augmented areas, Evidence of occlusal overload (i.e. occlusal contacts Plaque index (PI) <1 revealed appropriate adjustment), Implant mobility Wohlfahrt et al., 2012 BOP SUP PPD>5 mm BL >3 mm.

*PPD-Peri-implant probing depth; BOP- bleeding on probing; SUP-suppuration; BL-bone loss; SAT- systemic antibiotics; PIPD-peri-implant probing depth; RBL-radiographic bone loss; NSAIDS- non-steroidal anti-inflammatory drugs; CHX- chlorhexidine; HbA1c-glycelated haemoglobin; N-newton; PI-plaque index.

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Table 20: Summary of inclusion criteria described by the included studies

Function Implant RBL RBL RBL PPD PPD>/=5mm PPD BOP SUP KT OH al in >/= >2.5mm >3mm >/= >6mm Plaque implant function 2mm 4mm index for >2 years Carcuac et al., 2015 ✅ ✅ de Waal et al., 2012 ✅ ✅ ✅ ✅ ✅ de Waal et al., 2014 ✅ ✅ ✅ ✅ ✅

Esposito et al., 2013 ✅ ✅ ✅

Javed et al., 2016 ✅ ✅ ✅ ✅ ✅

Machtei et al., 2012 ✅ ✅ ✅

Papadopoulos et al., 2015 ✅ ✅ ✅

Persson et al., 2010 ✅ ✅ ✅ ✅ ✅

Renvert et al., 2011 ✅ ✅ ✅ ✅ ✅ ✅ ✅

Schwarz et al., 2007 ✅ ✅ ✅ ✅ ✅ ✅

Schwarz et al., 2011 ✅ ✅ ✅ ✅ ✅ ✅

Schwarz et al., 2012 ✅ ✅ ✅ ✅ ✅ ✅

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Schwarz et al., 2013 ✅ ✅ ✅ ✅ ✅ ✅

Wohlfahrt et al., 2012 ✅ ✅ ✅

*PPD-Peri-implant probing depth; BOP- bleeding on probing; SUP-suppuration; BL-bone loss; SAT- systemic antibiotics; PIPD-peri-implant probing depth; RBL-radiographic bone loss; NSAIDS- non-steroidal anti-inflammatory drugs; CHX- chlorhexidine; HbA1c-glycelated haemoglobin; N-newton; PI-plaque index; KT- keratinised tissue; OH-oral hygiene.

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Table 21: Summary of exclusion criteria described by the included studies

acute acute

CHX disease Hollow Hollow

implant NSAIDs margins cylinder cylinder Occlusal Occlusal Mobility Smokers required overload Systemic Systemic Allergy to Allergy Antibiotics Antibiotics Presence of Presence periodontitis

overhangs or overhangs or Signs of Failed implants Failed

Carcuac et al., 2015 ✅

de Waal et al., 2012 ✅ ✅ ✅

de Waal et al., 2014 ✅ ✅ ✅ ✅

Esposito et al., 2013 ✅ ✅ ✅ Javed et al., 2016 ✅ ✅ ✅ Machtei et al., 2012 ✅ ✅ ✅ Papadopoulos et al., 2015

✅ Persson et al., 2010 Renvert et al., 2011 Schwarz et al., 2007 ✅ ✅ ✅ ✅ ✅ ✅ ✅ Schwarz et al., 2011 ✅ ✅ ✅ ✅ ✅ ✅ ✅

✅ ✅ ✅ ✅ ✅ ✅ ✅ Schwarz et al., 2012 Schwarz et al., 2013 ✅ ✅ ✅ ✅ ✅ ✅ ✅ Wohlfahrt et al., 2012

*CHX-chlorhexidine; NSAIDS - non-steroidal anti-inflammatory drugs

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4.4.5: Description of studies: Interventions

Tables 16 and 17 list study characteristics describing non-surgical and surgical interventions for the treatment of peri-implantitis respectively.

Methods to decontaminate the implant surface varied across the studies including debridement (Persson et al., 2010) with manual or ultrasonic instruments using carbon fibre, titanium (Wohlfahrt et al., 2012) or plastic tips (Schwarz et al., 2011), air-powder abrasive devices, laser treatment (Renvert et al., 2011; Esposito et al., 2013; Schwarz et al., 2012; Papadopoulos et al., 2015), and the systemic or local application of antimicrobials (Machtei et al., 2012; de Waal et al., 2012; de Waal et al., 2014; Carcuac et al., 2015; Javed et al., 2016).

Table 22: Treatment modality evaluated by included studies

Non-surgical interventions Persson et al., 2010

Javed et al., 2016 Adjunctive treatments to non-surgical interventions Machtei et al., 2012 Surgical vs non-surgical intervention with adjunctive Esposito et al., 2013 treatments Schwarz et al., 2013 Schwarz et al., 2012 Wohlfahrt et al., 2012 Surgical intervention Schwarz et al., 2011 Schwarz et al., 2007

Carcuac et al., 2015 Papadopoulos et al., 2015 Adjunctive treatments to surgical interventions de Waal et al., 2014 de Waal et al., 2012 Renvert et al., 2011

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4.4.6: Description of studies: Outcome measures

• Implant failure leading to loss or removal of the implant was evaluated in all studies. • Complications and side effects were reported in all studies except (Renvert et al., 2011). • Recurrence of peri-implantitis was reported in one of the studies (Esposito et al., 2013). • Peri-implant probing depth change was recorded across all of the studies. • The change in sites with bleeding on probing was recorded in all studies. • Plaque scores were recorded in 7 studies (Schwarz et al., 2007; Persson et al., 2010; Renvert et al., 2011; de Waal et al., 2012; Esposito et al., 2013; de Waal et al., 2014; Papadopoulos et al., 2015). • The change in number of sites with suppuration on probing was recorded in five studies (Renvert et al., 2011 de Waal et al., 2012; Esposito et al., 2013; de Waal et al., 2014; Carcuac et al., 2015). • Change in mucosal recession was not evaluated in any of the studies. • CAL was evaluated in six studies (Schwarz et al., 2007; Machtei et al., 2012; Schwarz et al., 2012; Schwarz et al., 2013; Papadopoulos et al., 2015; Javed et al., 2016). • Radiographic marginal bone levels measured from intraoral radiographs were evaluated in all studies except (Persson et al., 2010; Machtei et al., 2012; Papadopoulos et al., 2015). • Implant stability using resonance frequency analysis was recorded in one study (Wohlfahrt et al., 2012).

4.4.7: Description of studies: Follow up

The inclusion criteria for this review specified a minimum follow up time of 6 months.

Five studies had a follow up of 6 months (Schwarz et al., 2011; Persson et al., 2010; Renvert et al., 2011; Machtei et al., 2012; Papadopoulos et al., 2015).

Six studies had a follow up of 12 months (de Waal et al., 2012; Esposito et al., 2013; de Waal et al., 2014; Wohlfahrt et al., 2012; Carcuac et al., 2015; Javed et al., 2016). Two studies had a follow up of 24 months (Schwarz et al., 2007; Schwarz et al., 2012). One study had a follow up duration of 48 months (Schwarz et al., 2013).

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4.4.8: Description of studies: Sample size

Sample size ranged from 22 to 100 subjects across the 14 studies. 3 included studies reported on the same cohort at different follow up intervals (Schwarz et al., 2011; Schwarz et al., 2012; Schwarz et al., 2013).

A sample size determination calculation was described by six studies (Persson et al., 2010; Renvert et al., 2011; Machtei et al., 2012; Esposito et al., 2013; Carcuac et al., 2015; Javed et al., 2016).

4.4.9: Pre-treatment and maintenance

Table 23: Maintenance and preoperative treatments received by subjects of included studies

Peri-operative maintenance Study

All patients received OHI and MD of implants. Post op: 2/52 mouth wash mouth rinsing with de Waal et al., 2014 CHX, OHI at follow up. de Waal et al., 2012

Papadopoulos et al., 2015 Esposito et al., 2013 OHI at baseline and each follow up. Wohlfahrt et al., 2012 Persson et al., 2010 All subjects received OHI and received a sonic Renvert et al., 2011 toothbrush with new heads at 3 months. Schwarz et al., 2013 Post op rinsing with a 0.2% CHX 2x day 2/52. Schwarz et al., 2012 OHI at baseline and each follow up. Schwarz et al., 2011 Schwarz et al., 2007 OHI and preoperative MD of implants/teeth. Carcuac et al., 2015 OHI at each follow up. Machtei et al., 2012

No protocol described Javed et al., 2016

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Table 24: Sponsorship and source of funding for included studies

Sponsorship Study

Javed et al., 2016 Carcuac et al., 2015 Papadopoulos et al., 2015 de Waal et al., 2014 No declaration Machtei et al., 2012 Wohlfahrt et al., 2012 de Waal et al., 2012 Persson et al., 2010 Sponsored by CMS dental the manufacturers of FotoSan- however, sponsorship withdrawn when therapy shown to be ineffective. Sponsored by Electric Medical Systems and by Philips Renvert et al., 2011 Oral Healthcare (Snoqualmie, WA, USA). Schwarz et al., 2013 The study was supported by a grant from Heraeus, Schwarz et al., 2012 Hanau, Germany. The study materials were provided Schwarz et al., 2011 by Geistlich Biomaterials. Schwarz et al., 2007

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4.5 Quality assessment and risk of bias:

The Cochrane Collaboration tool was used to evaluate risk of bias. See appendices 26-39 for bias summary tables.

Figure 5: Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 6: Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Risk of Bias:

Figure 5 and 6 summarise the risk of bias for each of the included studies.

Six of the fourteen studies (Machtei et al., 2012; Wohlfahrt et al., 2012; Esposito et al., 2013; Javed et al., 2016; de Waal et al., 2012; de Waal et al., 2014) were determined to have unclear risk of bias by the author, eight were considered high risk and none were considered low risk.

Random sequence generation: Selection bias:

Computer generated randomisation was carried out in eleven studies (Schwarz et al., 2007; Persson et al., 2010; Renvert et al., 2011; Schwarz et al., 2011; de Waal et al., 2012; Machtei et al., 2012; Schwarz et al., 2012; Wohlfahrt et al., 2012; Schwarz et al., 2013; de Waal et al., 2014; Carcuac et al., 2015; Papadopoulos et al., 2015). One study described randomisation through sequentially numbered sealed envelopes (Esposito et al., 2013), one study (Javed et al., 2016) described randomisation sequence generation through a coin toss.

Allocation concealment: Selection bias:

Three studies (de Waal et al., 2012; Machtei et al., 2012; de Waal et al., 2014) clearly described allocation concealment and were considered low risk. Four studies (Schwarz et al., 2007; Persson et al., 2010; Carcuac et al., 2015; Javed et al., 2016) did not describe allocation concealment, thus, the risk of bias was unclear. One study (Papadopoulos et al., 2015) had no allocation concealment, the risk of bias was considered high.

Blinding: Performance and detection bias:

Two studies (de Waal et al., 2012; de Waal et al., 2014) had a double blinding method. Where all subjects and investigators were blinded. These studies were considered low bias risk.

In six studies (Schwarz et al., 2007; Renvert et al., 2011; Schwarz et al., 2011; Schwarz et al., 2012; Schwarz et al., 2013; Esposito et al., 2013) the investigator was blinded to the treatment but the subjects were not (single blinding).

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In three studies (Wohlfahrt et al., 2012; Carcuac et al., 2015; Papadopoulos et al., 2015) there was no blinding process described therefore bias risk was considered high.

Incomplete outcome data: Attrition bias

In one of fourteen studies (Renvert et al., 2011) all subjects completed the study.

Withdrawal from the study occurred in the other 13 studies.

In the study by Schwarz et al., (2007), data from 2 patients excluded at 12-months (due to severe pus formation) was not reported in final results. In the study by Schwarz et al., (2013), 11 subjects were discontinued from the study due to signs of reinfection.

Selective reporting-reporting bias:

Only one study was considered low risk (Renvert et al., 2011) as all data was reported. All other remaining studies were considered high risk due to missing data from excluded subjects or drop outs.

Other bias:

Table 24 shows sponsorship and funding sources for included studies.

Two studies were directly sponsored by commercial parties (Renvert et al., 2011; Esposito et al., 2013). Esposito et al., (2013) was sponsored by CMS dental (manufacturers of FotoSan), sponsorship was withdrawn when therapy was shown to be ineffective. Four studies (Schwarz et al., 2007; Schwarz et al., 2010; Schwarz et al., 2011; Schwarz et al., 2013) received part funding by Geistlich Biomaterials, with donation of all materials used. Eight studies did not declare any sponsorship or financial involvement from commercial parties or sources relating to the product being tested that may induce bias.

Many of the studies included multiple implants per patient, which has the potential to induce bias and data skewing. Only two studies considered only one implant per subject. Esposito et al., (2013) and Persson et al., (2010) who included multiple implants per patient for treatment but only 1 implant (worst affected) was recorded for the study to reduce bias.

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4.6 Comparative non-surgical interventions: Summary of findings Below the findings of included studies designed to assess non-surgical interventions with or without adjunctive therapy have been summarised.

Mechanical non-surgical treatment of peri-implantitis In a parallel design study, Persson et al., (2010), compared manual debridement using titanium curettes with the Vector ultrasound system. 37 subjects were enrolled in the study and 6 subjects were lost to follow up. At 6 months of follow up, implant success was 100% with no lost implants. It was concluded however there were no significant changes in either treatment groups for mean probing depth or BOP sites thus concluding neither treatment proved effective in the treatment of peri-implantitis. No significant differences were found between the two techniques. No information regarding RBL was reported.

Treatment of peri-implantitis using an Er: YAG laser or an air-abrasive device Renvert et al., (2011) evaluated 6-month outcomes following treatment with an Er: YAG laser (21 patients with 55 implants) compared with an air-abrasive device (21 patients, 45 implants) in a single masked randomised control study. BOP, suppuration, mean probing depths, peri-implant marginal bone gain/loss were recorded at baseline and at 6 months. All patients completed the study. No baseline subject characteristic differences were found. BOP and SUP decreased in both groups (p<0.001). Mean PPD reductions in the air abrasive group and Er: YAG laser groups were 0.9 mm (SD 0.8) and 0.8 mm (SD ± 0.5), with mean RBL of 0.1 mm (SD ± 0.8) and 0.3 mm (SD ± 0.9), respectively (NS). A positive treatment outcome, PPD reduction ≥0.5 mm and gain or no loss of bone was found in 47% and 44% in the AM and LM groups, respectively. The authors concluded clinical treatment results were limited and similar between the two methods compared.

Use of mechanical debridement with local application of antibiotics for non-surgical therapy of peri-implantitis.

Machtei et al., (2012) evaluated treatment in 60 patients (77 implants), comparing matrix chips (MatrixC) with CHX chips (PerioC) in a multi-centre, randomised, double-blind, parallel, two-arm clinical trial. After 6 months of treatment both groups showed improvement in PD, BOP, CAL. Probing depth reduction was greater in the PerioC (2.19 ± 0.24 mm) compared with MatrixC (1.59 ± 0.23 mm). Bleeding on probing was reduced by

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half in both groups and gains in clinical attachment were significant. The authors concluded that the use of MD with frequent local application of PerioC and MatrixC is a successful non-surgical therapy for peri-implantitis. Further studies were suggested to establish the mechanism of this treatment.

The adjunctive use of light-activated disinfection (LAD) with FotoSan In a multicentre pragmatic randomised controlled trial, Esposito et al., (2013) examined the effects of the adjunctive use of light-activated disinfection (LAD) in the treatment of peri- implantitis. 80 patients (80 implants) were non-surgically or surgically treated for peri- implantitis and 50% of them randomly allocated to receive an additional LAD treatment (FotoSan) according to a parallel group design at four different centres. Outcome measures were implant failures, recurrence of peri-implantitis, complications, peri-implant RBL, PPD changes and number of re-treatment sessions recorded by blinded assessors. Patients were followed up for 1 year after treatment. Five treated patients did not fit original inclusion criteria, 4 because they were not affected by the present definition of peri-implantitis and 1 due to being treated with antibiotics, results were calculated with and without these subjects. The authors concluded that the adjunctive use of LAD therapy (FotoSan) with mechanical cleaning of implants affected by peri-implantitis did not improve any clinical outcomes when compared to mechanical cleaning alone up to 1 year after treatment.

Mechanical debridement with and without adjunct antimicrobial photodynamic therapy Javed et al., (2016) conducted a randomised controlled study with 166 subjects to assess the efficacy of mechanical debridement (MD) with and without adjunct antimicrobial photodynamic therapy (aPDT) in reducing peri-implant inflammation among cigarette- smokers and non-smokers. Smokers and non-smokers received full mouth scaling and mechanical debridement. In the test group subjects received adjunct antimicrobial photodynamic therapy (aPDT). Outcomes including BOP, PD and RBL were recorded at baseline, 6 and 12 months. The study concluded that in the short-term (6-months), MD with adjunct aPDT is more effective in reducing peri-implant probing depth than MD alone in smokers and non-smokers. However, at 12 months outcomes of MD either with or without aPDT among smokers and non- smokers are comparable.

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4.7 Comparative surgical interventions:

Treatment of peri-implantitis lesions using a nanocrystalline hydroxyapatite or a natural bone mineral in combination with a collagen membrane. Schwarz et al., (2007) conducted a parallel-design, randomised controlled trial with a 24- month follow-up. With a regenerative surgical approach, it was demonstrated that both nanocrystalline hydroxyapatite and guided bone regeneration provided clinically significant improvements in clinical parameters following 6 months of non-submerged healing. In 22 subjects diagnosed with peri-implantitis, a full thickness mucoperiosteal flap was elevated and implant surface exposed. Granulation tissue from the implant defect was removed, implant surfaces debrided with plastic curettes and then irrigated with saline solution. Peri- implant defects were grafted with either a synthetic nanocrystalline hydroxyapatite (Ostim) or a bovine-derived xenogenic bone mineral (BioOss), and covered with a collagen membrane (Bio-Gide). No systemic antimicrobials were prescribed. Results did not allow for reliable statistical comparison of the efficacy of the two therapeutic procedures due to a small sample size of 22 subjects.

Combined surgical therapy of peri-implantitis evaluating two methods of surface debridement and decontamination. Schwarz et al., (2011; 2012; 2013) compared two surface decontamination methods in conjunction with regenerative surgical treatment. 32 subjects were included and followed up at 6 months (Schwartz et al., 2011), 2 years (Schwarz et al., 2012) and 4 years (Schwarz et al., 2013).

A full mucoperiosteal flap was raised and granulation tissue removed. Implants were randomly allocated to surface debridement with either (1) Er: YAG laser or (2) plastic curettes plus swabbing with cotton pellets soaked in saline and irrigation with saline. In both groups, the peri-implant defect was augmented with a xeno-genic bone mineral (Bio- Oss) and covered with a collagen membrane. Clinical parameters were recorded at baseline and after 6, 24 and 48 months of non-submerged healing across the 3 studies.

At 6 months, Schwartz et al., (2011) found ERL-treated sites failed to reveal higher reductions in mean bleeding on probing (ERL: 47.8 +/- 35.5 versus CPS: 55.0 +/- 31.1%) and CAL values (ERL: 1.5 +/- 1.4 versus CPS: 2.2 +/- 1.4 mm) when compared with the The professional management of peri-implantitis- a systematic review. 87

CPS group. Both groups exhibited a comparable radiographic bone fill at the intra-bony defect component.

At 24 months, Schwartz et al., (2012) found ERL treated sites failed to reveal significantly higher reductions in mean BOP (ERL: 75.0 ± 32.6% versus CPS: 54.9 ± 30.3%) and CAL values (ERL: 1.0 ± 2.2 mm versus CPS: 1.2 ± 2.2 mm) when compared with the CPS group. In both groups, mean CAL values were not significantly different when compared with baseline. There were 5 implants in both groups with recurrent peri-implantitis, which were retreated.

At 48 months, Schwartz et al., (2013) found CPS-treated sites tended to reveal higher reductions in mean BOP (CPS: 85.2 +/- 16.4% versus ERL: 71.6 +/- 24.9%) and CAL values (CPS: 1.5 +/- 2.0 mm versus ERL: 1.2 +/- 2.0 mm) when compared with the ERL group. In both groups, clinical outcomes were not directly influenced by the initial defect configuration

Decontamination during surgical peri-implantitis treatment In a randomised, double-blind, placebo-controlled trial, de Waal et al., (2012) evaluated the effect of implant surface decontamination with (CHX)/(CPC) for patients with peri- implantitis. 30 subjects (79 implants) were treated with resective surgical treatment consisting of apically re-positioned flap, bone re-contouring and surface debridement and decontamination. Patients were randomly allocated to decontamination with 0.12% CHX + 0.05% CPC (test-group) or a placebo-solution (without CHX/CPC, placebo-group). Outcomes including (BOP, PIPD, RBL, BOP, SUP) were recorded at baseline, 3,6 and 12 months. In the placebo-group 9 implants (from 2 patients) were lost due to severe persisting peri-implantitis. Both procedures resulted in significant reductions of bacterial load on the implant surface, but the test-group showed a significantly greater reduction than the placebo-group (log 4.21 ± 1.89 versus log 2.77 ± 2.12, p = 0.006). Multilevel analysis showed no differences between both groups for BOP, SUP, PPD and RBL over time. The study concluded neither treatment modality is superior in terms of clinical outcome measure.

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In a further randomised, double-blind, controlled trial de Waal et al., (2014) evaluated the effects of implant surface decontamination with a 2% CHX solution in comparison with a 0.12% CHX + 0.05% (CPC) solution during resective surgical peri-implantitis treatment. Forty-four patients (108 implants) with peri-implantitis were treated with the same procedure as described in the previous study (de Waal et al., 2012). Patients were randomly allocated to decontamination with a 2% CHX solution (test group) or 0.12% CHX + 0.05% CPC (control group). Clinical and radiographic parameters were recorded at baseline and at 3, 6, and 12 months after treatment. Multilevel analysis showed no significant differences in BOP, SUP, PPD, and RBL between control and test group over three follow-up measurements (3, 6, and 12 months) from baseline. Both decontamination procedures resulted in significant reductions in anaerobic bacterial counts on the implant surface, but no significant difference was noted between control and test group (mean log 3.37 ± 2.34 vs. 3.65 ± 2.87, P = 0.99).

Porous titanium granules in the surgical treatment of peri-implant osseous defects In a prospective randomised controlled trial with a 12 month follow up, Wohlfahrt et al., (2012) evaluated outcome by adding (PTG) together with an OF procedure and in conjunction with mechanical debridement of the implant surface for decontamination with 24 % EDTA gel followed by antibiotics (amoxicillin and metronidazole) 3 days prior to surgery and for 7 days after surgery. Outcomes were measured at baseline and at 12 months. The outcomes measured were PPD, BOP, Implant stability (RFA) and RBL adverse effects were also recorded. Both treatments demonstrated significant improvements in probing pocket depth but the reconstruction with PTG resulted in better radiographic peri-implant defect fill.

The utilization of a diode laser in the surgical treatment of peri-implantitis Papadopoulos et al., (2015) conducted a randomised controlled trial with 19 subjects designed to compare the effectiveness of OF debridement with open flap debridement and the additional use of a diode laser for the treatment of peri-implantitis. A full thickness mucoperiosteal flap was raised at the infected implant site and the implant surface debrided using plastic curettes. Implant surfaces were treated using sterilised gauzes soaked in saline. In the test group subjects were exposed to additional diode laser treatment. Outcomes were recorded at baseline, 3 months and 6 months. The outcomes studied were PD (the primary outcome variable), CAL, BOP and PI. The study failed to The professional management of peri-implantitis- a systematic review. 89

reveal any significant clinical improvements in mean BOP and PD scores at 6 months, thus, concluding that the additional use of a diode laser in the surgical treatment of peri- implantitis offers limited clinical benefit.

Adjunctive Systemic and Local Antimicrobial Therapy in the Surgical Treatment of Peri-implantitis. A prospective randomised controlled clinical trial (Carcuac et al., 2015) investigated the adjunctive effect of systemic antibiotics (amoxicillin) and the local use of chlorhexidine 0.12% for implant surface decontamination in the surgical treatment of peri-implantitis. The study included 100 subjects (179 implants) with a 12 month follow up period. The local use of CHX 0.12% had no overall effect on treatment success (OR, 0.31; P = 0.209). The use of systemic antibiotics had no impact on treatment success at implants with a non-modified surface (OR, 0.27; P = 0.506), whereas at implants with a modified surface, a positive effect on treatment success was observed (OR, 38.69; P = 0.005). Whilst it is possible that positive effects may been observed when adjunctive systemic antibiotics are used on implants with a modified surface the strength of evidence for this is weak.

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4.8 Quantitative study results:

Table 25: Study results for radiographic bone level values.

Study Baseline bone level (mm) Bone level at 6 months (mm) Bone level at 12 months (mm) 4.9 mm (SD 0.8) Study group 1: 5.1 mm (SD 0.6) Persson et al., 2010 4.9 mm (SD 0.9), No data Study group 2: 5.2 mm (SD 0.7)

Laser group at 6 months: a loss of 0.3 mm (SD +0.9) Renvert et al., 2011 Air abrasion group at 6 months: a loss of 0.1 mm (SD ±0.8) Machtei et al., 2012 No data No data No data LAD: Change 0 (SD 1.33) Esposito et al., LAD: 4.5 (SD 1.75) Not recorded Control: Change -0.13 SD (1.27) 2013 Control: 4.9 (SD 2.07)

Data presented in graphical form. No table form data for mean or standard Javed et al., 2016 deviations.

In both treatment groups, radiological observation at 24 months revealed a Schwarz et al., decreased translucency within the intra- 2007 bony component of the respective peri- implant bone defects.

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Schwarz et al., No data No data No data 2011 Placebo: 3.6 (1.9) 4.3 (2.2) 3.9 (2.6) de Waal et al., 2012 Test: 4.3 (2.1) 4.9 (2.4) 5.0 (2.5) Wohlfahrt et al., PTG: 5.4 (1.5) PTG: 2.7 (1.3) No data 2012 OFG: 4.3 (1.3) OFG: 3.2 (1.4) Schwarz et al., No data No data No data 2013 Control: 4.1 (1.6) Control: 4.2 (1.7) Control: 4.1 (1.7) de Waal et al., 2014 Test: 4 (1.5) Test: 4.3 (1.6) Test: 4.3 (1.7) Papadopoulos et al., No data No data No data 2015 12 months: Change: Group 1: 0.18 (1.15) 12 months: Change Group 2: 0.51 (0.84) Carcuac et al., 2015 12 months: Change Group 3: -0.69 (1.32) 12 months: Change Group 4: -0.96 (1.42) Schwarz et al., No data No data No data 2012

Bone level in (mm) given as mean and standard deviation.

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Table 26: Study results for pocket probing depth (PPD).

Probing pocket depth Probing pocket depth (6 Probing pocket PD 24 PD 48 Study (baseline) months) depth (12 months) months months Group 1: 5.1 (0.6) Group 1: 4.9 (0.8) Persson et al., 2010 No data No data No data Group 2: 5.2 (0.7) Group 2: 4.9 (0.90 Laser group: change at 6 months 0.8 mm (SD ±0.5), Renvert et al., 2011 No data No data Air abrasion group: change at 6 months 0.9 mm (SD ±0.8). Perio C: 7.60mm Perio C: 5.47mm Machtei et al., 2012 MatrixC: 7.21mm MatrixC: 5.48mm No data No data No data

LAD: 5.14 (SD 1.83) LAD: 6.23 (SD 1.62) LAD: 5.08 (SD 1.63) Control: 5.5 (SD Esposito et al., 2013 Control: 6.45 (SD 2.15) Control: 5.25 (SD 1.63) No data No data 1.94) *4 months

Data presented in graphical form. No table form data for mean or standard deviations. Javed et al., 2016

Test: 6.9 (SD 0.6) 4.9 (0.8) 5.4 (0.7) Schwarz et al., 2007 No data No data Control: 7.1 (SD 0.8) 4.4 (0.6) 4.7 (0.7) CPS: 5.5 (1.8) CPS: 3.1 (0.6) Schwarz et al., 2011 No data No data No data ERL: 5.1 (1.6) ERL: 3.4 (0.6) Placebo: 5.5 (1.4) Placebo: 4.1 (1.4) Placebo: 3.7 (0.8) de Waal et al., 2012 No data No data Test: 6.6 (1.6) Test: 4.0 (1.5) Test: 4.3 (2.1) PTG: 8 (1.7) PTG: 5.3 (1.9) Wohlfahrt et al., 2012 No data No data No data OFG: 8 (2.8) OFG: 4.5 (2.1)

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CPS: 4.3 CPS: 5.5 (1.7) CPS: 3.1 (0.6) (1.2) Schwarz et al., 2013 No data No data ERL: 5.1 (1.5) ERL: 3.4 (0.6) ERL:3.8 (1.1) Control: 5(1.2) Control: 2.9 (0.8) Control: 2.9 (0.7) de Waal et al., 2014 No data No data Test: 4.7 (1) Test: 2.8 (0.6) Test: 3 (0.7) Control: mean 1.19mm reduction at 6 months Papadopoulos et al., 2015 Laser: mean 1.38mm reduction at 6 months Group 1: Group 1: Group 1: Group 2: Group 2: Group 2: Carcuac et al., 2015 No data No data Group 3: Group 3: Group 3: Group 4: Group 4: Group 4: CPS: 5.2 (1.5) CPS: 3.2 (0.4) CPS: 3.7(1.1) Schwarz et al., 2012 No data No data ERL: 4.9 (1.4) ERL: 3.2 (0.8) ERL: 3.8 (1.3) Pocket depth values in (mm) given as mean and standard deviation.

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Table 27: Study results for bleeding on probing (BOP).

Bleeding on Bleeding on probing Bleeding on Study probing (12 24 months 48 months (baseline) probing (6 months) months) Group 1: all implants presented with bleeding on probing. At month 6, three of these implants presented with no evidence of bleeding on Persson et al., 2010 probing. No data No data Group 2: all implants presented with bleeding on probing. At month 6, two of these implants presented with no evidence of bleeding. BOP at baseline 5.1% surfaces show4ed a point of bleeding. 37.8% a line of bleeding. 57.1% a drop of Renvert et al., 2011 bleeding. 6 months: no bleeding at 30.9% implant in laser group. No bleeding at 25% of implants in air abrasive group. Perio C: 100% Perio C: 57.5% Machtei et al., 2012 No data No data No data MatrixC: 100% MatrixC: 41% LAD: 1.03 (SD 1.33) LAD: 1.35 (SD 1.32) LAD: 2.95 (SD 1.32) Esposito et al., 2013 Control: 1.1 (SD Control: 1.28 (SD No data No data Control: 2.68 (SD 1.25) 1.33) 1.11) (4 months) Javed et al., 2016 Data presented in graphical form. No table form data for mean or standard deviations. Test: 80% Test: 36% Test: 44% Schwarz et al., 2007 No data No data Control: 78% Control: 29% Control: 34% CPS: 100 (0) CPS: 45 (31.2) Schwarz et al., 2011 No data No data No data ERL: 93.3 (18.7) ERL: 45.5 (33) Placebo: 79.7% (28.1) Placebo: 60.1% (32) Placebo: 57.2% (29) de Waal et al., 2012 No data No data Test: 80.4% (26.5) Test: 54% (36.6) Test: 60.5% (30.1)

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PTG: 92% PTG: 77% Wohlfahrt et al., 2012 No data No data No data OFG: 100% OFG: 83% CPS: 14.8 CPS: 100 (0) CPS: 45 (31.2) (16.4) Schwarz et al., 2013 No data No data ERL: 93.3 (18.7) ERL: 45.5 (33) ERL: 23.5 (23.4) Control: 12.8 (12.6) Control: Control: de Waal et al., 2014 No data No data Test: 15.3 (15.2) Test: Test: Control group: BOP reduction 72.9% at 6 months Papadopoulos et al., 2015 Laser group: BOP reduction 66.7% at 6 months Group 1: 16 (34) Group 1: 18 (39.1) Group 2: 24 (52.2) Group 2: 16 (34.8) Carcuac et al., 2015 No data No data Group 3: 26 (56.5) Group 3: 20 (44.4) Group 4: 26 (74.3) Group 4: 18 (51.4) CPS: 100(0) CPS: 39.9 (26.6) CPS: 45.1 (30.4) Schwarz et al., 2012 No data No data ERL: 96.6 (10.6) ERL: 41.6 (27.5) ERL: 21.6 (33.3)

*Bleeding on probing as % sites given as mean and standard deviation.

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Table 28: Study results for suppuration on probing (SUP).

Suppuration on probing Suppuration on probing Suppuration on probing (12 Study (baseline) (6 months) months) Persson et al., 2010 No data No data No data 10.9% Laser: 30.9% Renvert et al., 2011 11.1% No data Air abrasive: 31.1%

Machtei et al., 2012 Outcome not reported Outcome not reported Outcome not reported Esposito et al., 2013 Outcome not reported Outcome not reported Outcome not reported Javed et al., 2016 Outcome not reported Outcome not reported Outcome not reported Schwarz et al., 2007 Outcome not reported Outcome not reported Outcome not reported Schwarz et al., 2011 Outcome not reported Outcome not reported Outcome not reported Placebo: 14.6 (25.2) Placebo: 1.6 (6.2) Placebo: 4.4 (11.2) de Waal et al., 2012 Test: 31.7 (31.6) Test: 5.6 (12.4) Test: 14.5 (28) Wohlfahrt et al., 2012 Outcome not reported Outcome not reported Outcome not reported Schwarz et al., 2013 Outcome not reported Outcome not reported Outcome not reported Control: 20.3 (25.6) Control: 2.3 (8.8) Control: 0.5 (3.4) de Waal et al., 2014 Test: 21.9 (24.8) Test: 1.6 (0.8) Test: 2.5 (7.7) Papadopoulos et al., 2015 Outcome not reported Outcome not reported Outcome not reported Group 1: 34 (72.3) Group 1: 5(10) Group 1: 6 (13) Group 2: 30 (65.2) Group 2: 2(4.3) Group 2: 3 (6.5) Carcuac et al., 2015 Group 3: 33 (67.3) Group 3: 9 (19.6) Group 3: 9 (25.7) Group 4: 26 (70.3) Group 4: 10 (22.2) Group 4: 11 (31.4) Schwarz et al., 2012 Outcome not reported Outcome not reported Outcome not reported *Suppuration on probing as % sites given as mean and standard deviation

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Table 29: Study results for clinical attachment loss (CAL) CAL (6 CAL (12 Study CAL (baseline) CAL (24 months) CAL (48 months) months) months) Outcome not Outcome not Outcome not Outcome not Persson et al., 2010 Outcome not reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Renvert et al., 2011 Outcome not reported reported reported reported reported Change at 6 months PerioC: 2.18(0.22) Outcome not Outcome not Outcome not Machtei et al., 2012 Change at 6 months MatrixC 1.69 (0.21) reported reported reported Outcome not Outcome not Outcome not Outcome not Esposito et al., 2013 Outcome not reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Javed et al., 2016 Outcome not reported reported reported reported reported Test: 5.7(0.9) Test: 6.3(0.9) Test: 7.3 (0.8) Outcome not Outcome not Schwarz et al., 2007 Control: 5.1 (0.7) Control: 5.5 (1) Control: 7.5 (1) reported reported

Outcome not Outcome not Outcome not Outcome not Schwarz et al., 2011 Outcome not reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not de Waal et al., 2012 Outcome not reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Wohlfahrt et al., 2012 Outcome not reported reported reported reported reported CPS: 6.7 (1.8) Outcome not Outcome not Outcome not CPS: 5.2 (1.9) Schwarz et al., 2013 ERL: 7.3 (1.9) reported reported reported ERL: 6.1(1.1) Outcome not Outcome not Outcome not Outcome not de Waal et al., 2014 Outcome not reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Papadopoulos et al., 2015 Outcome not reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Carcuac et al., 2015 Outcome not reported reported reported reported reported

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Table 30: Study results for plaque index (PI). Plaque index Plaque index (6 Plaque index (12 Plaque index Plaque index (48 Study (baseline) months) months) (24 months) months) Group 1: 91% Group 1: 37% Outcome not Outcome not Outcome not Persson et al., 2010 Group 2: 82% Group 2: 38% reported reported reported Outcome not Outcome not Outcome not Outcome not Outcome not Renvert et al., 2011 reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Outcome not Machtei et al., 2012 reported reported reported reported reported LAD: 0.89 (0.94) LAD:2.18 (1.53) Outcome not Outcome not Outcome not Esposito et al., 2013 Control: 0.93 Control:2.15 (1.64) reported reported reported (0.94) Outcome not Outcome not Outcome not Outcome not Outcome not Javed et al., 2016 reported reported reported reported reported Test: 1.3 (0.5) Test: 0.6 (0.5) Outcome not Test: 0.8 (0.6) Outcome not Schwarz et al., 2007 Control: 1.2 Control: 0.8 (0.4) reported Control: 0.9 (0.5) reported (0.9) Outcome not Outcome not Outcome not Outcome not Outcome not Schwarz et al., 2011 reported reported reported reported reported Placebo: 17.7 (26.3) Placebo:28.7(28.5) Placebo:15.8 (17.8) Outcome not Outcome not de Waal et al., 2012 Test: 9.7 (30.1 Test:18.6(24.1) Test:12.9(19.2) reported reported Outcome not Outcome not Outcome not Outcome not Outcome not Wohlfahrt et al., 2012 reported reported reported reported reported CPS: 0.8 (0.4) Outcome not Outcome not Outcome not CPS: 0.8 (0.7) Schwarz et al., 2013 ERL: 0.4 (0.5) reported reported reported ERL: 0.8 (0.7) de Waal et al., 2014 Control: 25 (30.8) Control: 26.9 (34.3) Control: 19.9 Outcome not Outcome not

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Test: 21.9 (33.7) Test: 7.3 (14.5) (29.7) reported reported Test: 15.1 (26.2) Outcome not Outcome not Outcome not Outcome not Outcome not Papadopoulos et al., 2015 reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Outcome not Carcuac et al., 2015 reported reported reported reported reported Outcome not Outcome not Outcome not Outcome not Outcome not Schwarz et al., 2012 reported reported reported reported reported

*All of the figures represent data at the patient level as opposed to the implant level. Data software ‘Review Manager (RevMan)’ was used for the calculation of confidence intervals and mean differences and construction of forest plots.

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4.9 Statistical analysis of data:

4.9.1 Analysis 1 Figure 7: Forest plot of comparison: LAD laser vs manual debridement. Outcome: Change in radiographic bone level at 12 months. Esposito et al., 2013

4.9.2 Analysis 2

Figure 8: Forest plot of comparison: LAD laser vs manual debridement. Outcome: Change in Probing depths at 12 months. Esposito et al., 2013

4.9.3 Analysis 3

Figure 9: Forest plot of comparison: Treatment of peri-implantitis using a laser or an air- abrasive device, outcome: Change in Radiographic bone level at 6 months from baseline. Renvert et al., 2011

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4.9.4 Analysis 4:

Figure 10: Forest plot of comparison: Treatment of peri-implantitis using a laser or an air- abrasive device: outcome: Change in Probing depths at 6 months from baseline. Renvert et al., 2011

4.9.5 Analysis 5

Figure 11: Forest plot of comparison: Treatment of peri-implantitis using Er: YAG laser versus air-abrasive device. Outcome: Recurrence of peri-implantitis at 6 months. Renvert et al., 2011

4.9.6 Analysis 6

Figure 12: Forest plot of comparison: Treatment of peri-implantitis using ERL vs CPS manual debridement: outcome: CAL changes at 6,24,48 months from baseline. Schwartz et al., 2011, 2012, 2013

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4.9.7 Analysis 7

Figure 13: Forest plot of comparison: Treatment of peri-implantitis using ERL vs CPS manual debridement: outcome: PPD changes at 6,24,48 months from baseline. Schwartz et al., 2011, 2012, 2013

4.9.8 Analysis 8:

Figure 14: Forest plot of comparison: Treatment of peri-implantitis using nanocrystaline hydroxyapatite vs natural bone mineral in combination with a collagen membrane. 12 and 24 months follow up. Outcome: Change in PPD. Experimental = NHA, nanocrystalline hydroxyapatite. Control = NBM+CM, natural bone mineral in combination with a collagen membrane. Schwarz et al., 2007.

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4.9.9 Analysis 9:

Figure 15: Forest plot of comparison: Treatment of peri-implantitis using nanocrystaline hydroxyapatite vs natural bone mineral in combination with a collagen membrane. 12 and 24 months follow up. Outcome: Change in CAL. Experimental = NHA, nanocrystalline hydroxyapatite Control = NBM+CM, natural bone mineral in combination with a collagen membrane. Schwarz et al., 2007.

4.9.10 Analysis 10:

Figure 16: Forest plot of comparison: Treatment of peri-implantitis using implant surgical root planning with application of matrix chips (MatrixC or chlorhexidine chips (PerioC) 6 months follow up. Outcome: Change in PPD. Macheti et al., 2012

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4.9.11 Analysis 11:

Figure 17: Forest plot of comparison: Treatment of peri-implantitis using implant surgical root planning with application of matrix chips (MatrixC or chlorhexidine chips (PerioC) 6 months follow up. Outcome: Change in CAL. Macheti et al., 2012

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Chapter Five- Discussion

The primary aim of this review was to systematically appraise available literature in order to evaluate the effectiveness of treatment for peri-implantitis in patients with functional osseointegrated dental implants. The secondary aim was to provide clinical guidelines for treatment based on the existing evidence base.

Whilst the true incidence of peri-implantitis is yet to be determined, disease prevalence is increasing. Regular monitoring and maintenance of peri-implant soft tissues is imperative with intervention utilised effectively in the presence of disease. Based on existing evidence, variation in the aetiology and pathogenesis of peri-implantitis compared with periodontitis has been identified.

The importance of prevention and prompt intervention in peri-implantitis has been demonstrated in the literature (Schwartz et al., 2008). If left untreated late implant failure may occur (Heitz-Mayfield, 2008; Canullo et al., 2015). The literature describes a number of protocols for prevention, treatment and management of peri-implantitis in an attempt to elucidate the most effective treatment approach. Whilst successful short-term outcomes have been demonstrated with several treatment modalities, no superior treatment protocol has been determined.

“Peri‐implantitis sites exhibit clinical signs of inflammation, bleeding on probing, and/or suppuration, increased probing depths and/or recession of the mucosal margin in addition to radiographic bone loss” (Berglundh et al., 2018). The desired outcome for treatment of peri-implantitis is resolution of disease. At the implant level this translates to a reduction in peri-implant probing depths, nil bleeding or suppuration on probing and stability of radiographic bone levels with no further bone loss.

Treatments described in the literature are broad: non-surgical therapy which includes mechanical debridement with or without adjunctive therapies and surgical interventions which may include open or closed debridement with or without regenerative or resective procedures (implantoplasty). Regenerative procedures include bone grafts or substitutes with or without barrier membranes. This systematic review performed a diligent evaluation of any accessible literature up to and including January 2007 until October 2017.

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Randomised controlled trials on the efficacy of all treatment modalities for the management of peri‐implantitis were critically analysed. Fourteen parallel deign randomised controlled trials were included. Each study was appraised and relevant findings discussed.

5.1 Summary of findings

Until now, no ‘gold standard’ intervention has been established for the treatment of peri‐implantitis. Many studies of varying levels of evidence exist. In general, the number of clinical studies and randomised controlled trials are limited in number, have short follow up periods and small sample sizes. Wide variation in methodology and reported outcomes make it difficult to perform meta-analysis in systematic reviews. No randomised controlled trial has been performed using a placebo group as it is unlikely ethical approval would ever be granted for such a study.

It is known from available literature treatment outcomes are likely to be determined by a number of systemic and local factors. Across available studies, variation in disease severity, implant design and surface characteristics make findings difficult to apply to all peri- implant lesions.

5.1.1: Non-surgical treatment for peri-implantitis

A plethora of non‐surgical interventions (with or without adjunctive therapy) have been described across the literature. Observation periods generally range from 3 months to 12 months. The number of patients in included studies is often relatively small, resulting in a low statistical power for detecting true differences between interventions. The type and frequency of maintenance care during the follow‐up phase of studies is not consistent, introducing potential confounding issues. Screw shaped designs and surface modifications of dental implants can pose challenges in effective mechanical non-surgical therapy. Studies included in this review reported conclusions consistent with the body of literature, which is that very little benefit is reported.

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Non-surgical debridement

Although many studies describing non-surgical mechanical management of peri-implantitis have limitations (short duration follow up, small sample sizes, unclear risk of bias), mechanical debridement alone does not seem an adequate modality for the resolution of all peri‐implantitis lesions. Hayek et al., (2005) and Karring et al., (2005) demonstrated mechanical sub‐mucosal debridement only was not sufficient for the decontamination of implant surfaces with peri‐implant pockets > 5 mm. Randomised controlled clinical trials with longer follow‐up periods and a higher number of participants are required in order to provide stronger evidence for this conclusion.

Persson et al., (2010) in this review, failed to show any significant differences comparing manual debridement using titanium curettes with the Vector ultrasound system. Thirty- seven subjects were enrolled in the study with six lost to follow up. At a six-month follow up, no significant changes in clinical parameters were found (mean probing depth or BOP sites) thus concluding neither treatment proved effective in the treatment of peri-implantitis. No information regarding radiographic bone loss was reported.

Successful long-term outcomes are likely to be influenced by the quality of maintenance care. It is therefore imperative all patients receive oral hygiene advice with regular supportive care.

Adjunctive treatment to non-surgical treatment of peri-implantitis

As non-surgical mechanical therapy alone does not appear to be effective in the management of peri-implantitis lesions, a number of studies have investigated the use of adjuncts to mechanical therapy. Adjunctive therapy may include: laser therapy, chemotherapeutics or antibiotics (systemic or local).

Laser therapy

The adjunctive use of laser therapy has been investigated with the aim to decontaminate the implant surface where mechanical instrumentation is not achievable. An in-vitro comparative study using titanium disks showed effective elimination of bacterial load using

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Er: YAG (Erbium-Doped Yttrium Aluminium Garnet), CO2 (Carbon Dioxide Laser) and Diode lasers (Tosun et al., 2012).

A comprehensive literature review designed to assess the efficacy of adjunctive laser therapies concluded the relative effect of laser application could not be assessed (Smeo et al., 2018). The review found significant variation in study design with small sample sizes across ten reviewed studies. Despite the results of this review, the therapeutic potential of lasers has been documented. Schwarz et al., (2006) reported positive outcomes (improved PPD, CAL, BOP) after six months follow-up with the use of laser therapy however, it was concluded that “a single course of non‐surgical treatment of peri‐implantitis using ERL may not be sufficient for the maintenance of failing implants” (Schwarz et al., 2006).

Renvert et al., (2011), a study included in this systematic review demonstrated the use of the Er: YAG laser appears to be an effective modality for the treatment of peri‐implantitis on a short‐term basis of six months demonstrated by improvements in clinical parameters. During this study, the plaque index of patients improved. Another interpretation of results could be that oral hygiene measures were initially less than adequate and an inability to control peri‐implant inflammation was the result of insufficient plaque control.

Positive treatment outcomes provide a foundation for future research. Further well‐designed randomised controlled clinical trials are required to assess whether these positive short‐term clinical outcomes can be maintained or if repetitive use is required at regular intervals. Future longer-term studies should focus on maintenance and an effective plaque control regime.

LAD: Photodynamic therapy

In a multicentre pragmatic randomised controlled trial Esposito et al., (2013) examined the effects of the adjunctive use of light-activated disinfection (LAD) in the treatment of peri- implantitis. The adjusted results showed that that the adjunctive use of LAD therapy (FotoSan) with mechanical cleaning of implants affected by peri-implantitis did not improve any clinical outcomes when compared to mechanical cleaning alone up to 1 year after treatment.

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Javed et al., (2016) conducted a randomised control study with 166 subjects to assess the efficacy of mechanical debridement (MD) with and without adjunct antimicrobial photodynamic therapy (aPDT) in reducing peri-implant inflammation among cigarette- smokers and non-smokers. The study concluded that in the short-term (six months), MD with adjunct aPDT is more effective in reducing peri-implant probing depth than MD alone in smokers and non-smokers. However, at 12 months outcomes of MD either with or without aPDT among smokers and non-smokers are comparable.

Both studies were considered low risk of bias, both trials conducted a power calculation for sample size and had a large number of subjects. From the evidence presented in both studies included in this review it is reasonable to suggest that currently there is little or no benefit for the adjunctive use of LAD therapy with mechanical cleaning for the management of peri-implantitis.

Antiseptic agents

One of the included studies evaluated the adjunctive use of antiseptic agents with non- surgical debridement. Machtei et al., (2012) compared matrix chips (MatrixC) with chlorhexidine chips (PerioC) in a multi-centre, randomised, double-blind, parallel, two-arm clinical trial. After 6 months of treatment both groups showed improvement in PD, BOP, CAL. Bleeding on probing was reduced by half in both groups and gains in clinical attachment were significant. The authors concluded that the use of mechanical debridement with frequent local application of PerioC and MatrixC is a successful non-surgical therapy for peri-implantitis.

In the wider body of literature, Schwarz et al., (2005) demonstrated that mechanical debridement with plastic curettes and adjunctive antiseptic (0.2% Chlorhexidine) may lead to statistically significant improvements in bleeding on probing, peri‐implant PPD and CAL at 6 months. No information was given regarding bone levels. In a separate study with a similar design, Schwarz et al., (2006) showed similar trends.

In a study by Renvert et al., (2006), it was concluded that adjunctive antiseptic therapy to mechanical debridement does not provide adjunctive benefits in “shallow” peri‐implant

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lesions (mean PPD < 4 mm) but seems to provide additional clinical improvements in “deep” peri‐implant lesions (mean PPD > 5 mm). It is important to consider probing depth values at implant sites may be influenced by a variety of local factors including soft tissue thickness, vertical implant positioning and design of the implant-abutment connection (e.g. platform-switching).

There is a clear need for further randomised controlled clinical trials on this subject, ideally with a split mouth design and follow‐up period more than 12 months.

Local antibiotics as an adjunctive to non-surgical debridement

None of the studies included in this review evaluated the use of local antibiotic as an adjunctive to non-surgical mechanical cleaning. The literature describes a number of studies evaluating the adjunctive use of local antibiotics. Lang et al., (2000) showed reasonable substantivity of antimicrobial agent with the use of tetracycline fibres. Renvert et al., (2006) demonstrated the adjunctive benefits from the addition of minocycline to mechanical debridement tend to be greater, to a limited extent, than those achieved by the combined use of an antiseptic (chlorhexidine) and mechanical debridement. Whilst it may be of benefit in the short term, multiple and repeated applications may be required. A major limitation of this study is that the inclusion criteria specified that bone loss was not more than three implant threads. It is still open to question whether deeper peri‐implant lesions can be adequately treated non‐surgically by a combination of a local antibiotic and mechanical debridement. The efficacy of the combination of local antibiotics with mechanical debridement in the therapy of peri‐implantitis has to be investigated further in high powered, randomised controlled clinical trials.

5.1.2: Surgical treatment for peri-implantitis

Surgical treatment of peri-implantitis lesions may be performed in sites with pocket formation larger than 5 mm and concurrent bone loss. Heitz- Mayfield and Lang, (2008) stated that prior to surgical therapy any acute infection must be resolved and proper oral hygiene instituted. All studies included in this review described oral hygiene protocols employed.

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Nine studies in this review reported on the surgical treatment of peri-implantitis, employing either alternative measures for surface decontamination or augmentation therapy. In these studies, peri-implantitis was commonly defined by BOP and radiographic bone level changes. However, there was large variation in thresholds used to assess bone loss. In general, studies included small patient samples with short follow‐up periods.

Adjunctive systemic and local antimicrobial therapy in the surgical treatment of peri- implantitis

A prospective randomised controlled clinical trial (Carcuac et al., 2015) investigated the adjunctive effect of systemic antibiotics (amoxicillin) and the local use of chlorhexidine 0.12% for implant surface decontamination in the surgical treatment of peri-implantitis. The local use of chlorhexidine 0.12% had no overall effect on treatment success. The use of systemic antibiotics had no impact on treatment success at implants with a non-modified surface, whereas at implants with a modified surface, a positive effect on treatment success was observed. Whilst it is possible that positive effects may been observed when adjunctive systemic antibiotics are used on implants with a modified surface the level of evidence for this is low.

Antiseptic agents as an adjunct to surgical therapy de Waal et al., (2012; 2014) demonstrated that the use of a 2% CHX solution for implant surface decontamination during resective peri-implantitis therapy does not lead to improved clinical, radiographic, or microbiological results when compared with a 0.12% CHX + 0.05% CPC solution.

The authors suggested that although the adjunctive use of CHX reduces anaerobic bacterial load at the implant surface more effectively than mechanical debridement alone, it does not seem to have an effect on clinical treatment outcomes (bleeding, suppuration, probing pocket depth, and radiographic bone loss) at 12 months.

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Laser therapy as an adjunct to surgical therapy

Schwarz et al., (2011, 2012, 2013) evaluated and compared the efficacy of surface debridement/decontamination (DD) using an Er: YAG laser (ERL) with that of plastic curettes and cotton pellets (CPS) soaked in sterile saline. The exposed implant surface was augmented with a natural bone mineral and covered with a collagen membrane. After 24 months of treatment, the CPS group yielded significant reductions in bleeding on probing although radiographic bone fill at the intra-bony defect was the same in both groups. Clinical attachment values were not significantly different between groups.

Papadopoulos et al., (2015) compared open flap debridement with plastic curettes (control) with open flap debridement plus the adjunctive use of a 980-nm diode laser, across 19 subjects and failed to reveal significant clinical improvements in mean BOP and PD scores at 6 months.

From available studies, it is reasonable to suggest that whilst laser therapy can be used effectively as an adjunct to non-surgical mechanical debridement, further studies are required to determine laser-related parameters to yield the most favourable outcomes. Long term follow up studies are necessary to determine the longevity of treatment and if multiple treatment applications are required.

Regenerative surgical techniques

Schwarz et al., (2007) evaluated treatment of peri-implantitis lesions using either a nanocrystalline hydroxyapatite (NHA) or a natural bone mineral in combination with a collagen membrane (NBM+CM). The findings demonstrated that both techniques provided clinically significant improvements in clinical parameters at 6 months. The 2‐year results (Schwarz et al., 2008) of the same clinical study demonstrated clinically significant reductions of PPD and gains in CAL.

A combination of natural bone mineral and collagen membrane seemed to correlate with greater improvements in clinical parameters and was associated with a more predictable and enhanced healing outcome. This study had a relatively small sample size (22 subjects) and did not allow a reliable statistical analysis of the efficacy of the two therapeutic procedures.

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Two patients from the NHA group were excluded from the study due to severe pus formation at 12 months.

Wohlfahrt et al., (2012) evaluated the 12-month outcome of peri-implant defect grafting using porous titanium granules (PTG) with an open flap procedure against mechanical debridement of the implant surface for decontamination with 24 % ethylenediaminetetracetic acid gel and peri treatment systemic antibiotics. Both treatments demonstrated significant improvements in probing pocket depth but the reconstruction with PTG resulted in improved radiographic peri-implant defect fill. The changes in clinical parameters were not statistically different between reconstructed versus non-reconstructed osseous defects.

Seven years after surgical treatment of peri-implantitis, 17 individuals met for follow-up examination (Wohlfahrt et al., 2017). The study reported unpredictable results for both treatments at 7 years (not included in the present review as study fell outside of inclusion date range). Further studies investigating regenerative techniques for the management of peri-implantitis defects are needed.

Ressective surgical techniques

None of the studies included in this review discussed implantoplasty. Across the literature implantoplasty is described as a method to remove the micro- and macro-roughened implant surface to discourage bacterial colonisation.

Two randomised comparative clinical trials (Romeo et al., 2004, 2007) conducted over a three-year period, concluded that resective surgical procedures combined with implantoplasty could have a positive effect on the clinical parameters and survival rates of rough-surfaced implants affected by peri-implantitis. These findings, in their limited state, are positive and could be used to inform further research. These studies were not included in the present review as they did not meet the inclusion criteria for diagnostic criteria.

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Systemic antibiotics

The available body of literature does not describe any studies evaluating the effects of systemic antibiotics as a monotherapy for the treatment of peri-implantitis. Systemic antibiotics are always described as an adjunct to non-surgical or surgical interventions. Further randomised double-blind, placebo-controlled trials aiming to assess the clinical effects of systemic antibiotic therapy as an adjunct to non-surgical or surgical treatment of peri-implantitis would be of value. Many of the surgical procedures investigated include post-operative antibiotics as part of the treatment. This raises the pertinent question- what role do systemic antibiotics have on treatment outcomes. 5.2 Summary Findings in this review reinforced previous statements: further research is needed to reach definitive conclusions. In a Cochrane systematic review of randomised controlled trials (Esposito et al., 2013), no superior treatment for peri-implantitis was identified.

The studies included in the Cochrane review compared a range of different treatments, often with multiple treatments combined, making it difficult to evaluate the effectiveness of a single procedure. Ideal future studies would be randomised controlled trials with a placebo treatment or split mouth design study- although this may not be ethically approved. A randomised controlled trial comparing an intervention against a procedure considered to be effective as a control may be of value.

Studies should ensure that effective sample sizes are determined using power calculations. The definition of peri-implantitis should be quantified universally and used for all studies- allowing for ease of comparison. Confounding factors should be identified and accounted for.

Bias risk should be considered by ensuring randomisation of subjects and blinding of assessors and subjects where possible to minimise bias. Outcomes should ideally report resolution of disease as well as clinical parameters. Follow up should be over several years where possible.

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5.3 Quantitative analysis

Five included studies reported statistically significant outcomes. The remaining studies failed to report any difference in outcome between groups. Forrest plots were produced for studies where a summary statistic was available using either the mean difference or risk ratio. The forrest plot gives a graphical display of results comparing 2 different interventions (Figures 7-17). No meta-analysis was possible due to the heterogeneity of the data with different interventions and outcomes reported across included studies. The lack of standardised treatment outcomes makes meta-analysis difficult if not impossible, thus limiting the power of high level systematic reviews.

5.4 Qualitative analysis

Qualitative analysis revealed significant heterogeneity between included studies and an overall, low evidence-grade. Specific causative factors for positive/negative outcomes could not be identified.

5.5 Critical Appraisal of Evidence

A universal criterion to diagnose peri-implantitis does not currently exist. Across the studies included in this review there was significant variation in parameters used to define peri- implantitis. Severity of disease also varied between studies and within studies. It is likely that successful treatment outcomes and prognoses are determined by the extent of the disease thus, the outcomes must be interpreted with this in mind. It is this authors’ opinion that a universal diagnostic criterion should be used across the literature. The criterion should define a pocket depth threshold and a threshold for pathological bone loss. Variation in definitions between studies may exclude implants/subjects that in other studies would have been diagnosed as peri-implantitis, possibly giving an unknown number of false negatives.

Different aetiological factors contribute to the development of peri-implant disease, with available evidence supporting increased risk in subjects with a history of chronic

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periodontitis, poor plaque control and no maintenance. There is also some evidence to suggest smoking and diabetes as potential risk factors/indicators for peri‐implantitis. Due to a multifactorial aetiology, there are a number of confounding variables to consider. Specific inclusion and exclusion criteria for studies included in this review are summarised in Tables 19 and 21.

Inclusion criteria All of the studies were human studies of adult populations with one or more osseointegrated implants in function affected by peri-implantitis. Two of the studies specified a minimum of two years in function for inclusion (de Waal et al., 2012; de Waal et al., 2014).

Exclusion criteria

Across included studies subjects were excluded for the following reasons:

• Poorly controlled diabetes • Smokers >/=10 cigarettes per day • Presence of periodontal pockets > 5 mm • Pregnant or lactating females • Subjects taking bisphosphonate medication • Subjects who had taken systemic antibiotics in recent months prior to treatment • Subjects with implants with < 2 mm keratinized mucosa or no keratinized mucosa • Subjects with a known allergy to chlorhexidine.

Due to variations in exclusion criteria, results from each study may not be generalised to the entire population.

During the initial review of papers, the main reason for exclusion was that there was a lack of clear distinction between peri-implantitis and peri-implant mucositis. Prior to exclusion the authors were contacted to determine the diagnostic criteria used. Several authors failed to respond to repeated requests for additional data, which limited data available for analysis.

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Sample size Across fourteen included studies a total of 635 subjects were included. Sample size ranged from 22 to 168 subjects. Only six of the fourteen studies used a power calculation to estimate statistical significance between test and control groups. In the included studies sample sizes were small thus making it difficult to determine significance between different treatment groups. Recruitment for trials may be challenging due to the large number of subjects required.

Intervention Across the studies included in this review different interventions and combinations of interventions were assessed which made it difficult to directly determine the effectiveness of each individual procedure.

Outcomes Implant failure leading to loss or removal of the implant, peri-implant probing depth and bleeding on probing was recorded in all studies.

Radiographic marginal bone levels measured from intraoral radiographs were evaluated in all studies except Persson et al., (2010; Machtei et al., (2012) and Papadopoulos et al., (2015). Currently, the literature does not suggest a superior criterion for the assessment of peri-implant disease progression.

It is well documented patients with poor plaque control are at increased risk of peri- implantitis (Berglundh et al., 1992; Lindhe and Meyle, 2008). This association has been shown to be dose dependant (van Steenberghe et al., 1993; Ferreira et al., 2006). Plaque scores were recorded in 7 included studies (Schwarz et al., 2007; Persson et al., 2010; Renvert et al., 2011; de Waal et al., 2012; Esposito et al., 2013; de Waal et al., 2014; Papadopoulos et al., 2015). In studies where plaque scores were either not recorded or not adequate, treatment outcomes may have been influenced by insufficient plaque control.

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Follow up Follow up periods for included studies ranged from 6 to 48 months. Whilst some positive results were shown, long-term effects are unknown. It may be that repeat interventions are required at varying intervals for effective long-term outcomes.

An interesting consideration is that after 12 months follow-up clinical parameters suggest relapse. Is this failure of the initial treatment or a recurrence of new disease activity for other reasons? Clearly, long-term follow up over 5-10 years with regular intervals for review/data collection would be of value.

Antibiotics The use of antibiotics during therapy is another factor that could affect results, as these can decrease the bacterial load in the short-term. Many surgical protocols described the use of adjunctive postoperative systemic antibiotics. There are no randomised controlled trials comparing treatment with or without systemic antibiotics.

Maintenance Maintenance protocols reported during and after the studies were inconsistent. No included study specifically described the prescribed oral hygiene regime. Successful treatment outcomes are likely to be influenced by the quality of maintenance care.

Four studies (Schwarz et al., 2007; Schwarz et al., 2011; Schwarz et al., 2012; Schwarz et al., 2013) specified subjects have a plaque index score of <1 for inclusion. This score was checked at each follow up, which is likely to promote a good standard of oral hygiene and maintenance care. The results indicate that subjects’ plaque scores were consistently good throughout the 48 months follow up period.

Other factors to be considered:

An important factor to consider is the influence of implant surface and design on treatment outcomes. Currently the “evidence for the influence of the implant surface characteristics as a risk indicator for peri-implantitis is very limited” (Heitz-Mayfield, 2008). A vast number of implant systems and designs exist each with variations in macro and micro

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structure. Astrand et al., (2004), reported that a TPS (titanium plasma spray) surface was reported to be more prone to peri-implantitis when compared with a turned surface.

The studies included in this review reported different implant manufactures and implant types; hollow implants were excluded by four of the studies (Schwarz et al., 2007; Schwarz et al., 2010; Schwarz et al., 2011; Schwarz et al., 2013). One study reported a positive effect on treatment success at implants with a modified surface (Carcuac et al., 2015). It may be that different implant surfaces may require different protocols for the management of peri- implantitis.

All of the studies included in this review were carried out in a University hospital setting. A question arises regarding the reality and practicality of these treatments in a general practice situation. In a research setting conditions are often ideal. Operator experience, which may have an influence of treatment outcome was not determinable from any of the studies.

Quality assessment and bias In this review, six studies were considered an unclear risk of bias. Eight studies were considered high risk of bias by the author. A sample size determination calculation was described by six studies (Persson et al., 2010; Renvert et al., 2011; Machtei et al., 2012; Esposito et al., 2013; Carcuac et al., 2015; Javed et al., 2016), power calculations should be performed to ensure an adequate sample size and avoid risk of bias.

Many of the studies included multiple implants per patient, this has the potential to induce bias and data skewing. Only one study (Esposito et al., 2013) considered one implant per subject. Persson et al., (2010) treated multiple implants per subject however only 1 implant (worst affected) was recorded for the study. In all of the studies where multiple implants per subjects were assessed a multivariate assessment was made to account for data bias.

When more than one implant per subject is being assessed a split mouth study design would be valuable.

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Withdrawals/drop outs Withdrawal of subjects from most of the studies was reported although reasons for withdrawal were not always described.

(Schwarz et al., 2007; Schwarz et al., 2010; Schwarz et al., 2011; Schwarz et al., 2013) withdrew subjects from the study that had recurrence of peri-implantitis. The subjects were retreated, however, the data outcomes of the retreatment was not recorded. These studies are considered high risk of bias as recurrence of peri-implantitis is considered an unsuccessful outcome however these subjects have been selectively removed from the study.

5.6 Recommendations: Clinical Practice

The existing evidence-base does not permit definitive conclusions to be reached on a ‘gold- standard’ treatment protocol.

With an increasing number of dental implants within the population the prevalence of peri- implant disease is likely to increase. Strategies for the prevention of peri-implant disease should be integrated into daily practice and considered most important. Given the available body of evidence a cumulative interceptive supportive therapy strategy should be adopted. See section 6.1-6.4 for the recommendations by this author based on the current body of evidence.

5.7 Recommendations: Future research

Limitations of currently available studies are: • Variation in definitions of peri-implant mucositis and peri-implantitis • multiple different treatment approaches • different implant designs as well as surface characteristics • short term follow-up and small sample sizes. • The absence of a true control group (no treatment or placebo) was identified as a common limitation however, there are ethical issues concerned with this considering available evidence suggests peri-implant disease should be treated early as progression can be rapid.

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There is a clear need for future research to definitively conclude the best treatment protocols.

Recommendations on areas of future research have been made throughout the discussion section.

5.8 Limitations of the current systematic review: Reflection

Only randomised controlled trials were included in this research project, however, none of the studies satisfy the true definition of a randomised controlled trial as none had a true control group (no treatment or placebo group). Although RCTs are considered to be high in the hierarchy of evidence, a number of factors decreased the quality level of the body of evidence. These factors include:

• limitations in the study design and methodology resulting in bias (lack of allocation concealment, lack of blinding, loss to follow up, withdrawal from study, selective outcome reporting). • Small sample sizes • Short term follow up

In terms of the systematic search, only one reviewer (author) conducted the review of available literature, which cannot be considered as reliable or accurate as multiple reviewers. Only English language articles were included in the search, which may have limited included studies.

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Chapter Six - Conclusions

From the findings of this systematic review, there is a lack of high strength evidence suggesting a superior intervention for the treatment of peri-implantitis. A combination of small sample sizes and short follow-up periods lead to a high risk of bias across included studies. Due to heterogeneity across included studies, findings must be interpreted in the context of inclusion and exclusion criteria as well as disease severity and definition.

Nine of fourteen included studies failed to show statistically significant differences between interventions. It is possible differences could not be determined due to insufficient sample sizes. From included studies there is low-level evidence to suggest some interventions can be successful in the short-term management of peri-implantitis.

Although the currently available evidence does not allow for specific recommendations, the following elements appear to be of benefit:

• Supportive pre- and post-operative management and maintenance to include: ▪ Oral hygiene advice (electric tooth brush with interdental hygiene aids). ▪ Smoking cessation advice ▪ Identification of systemic disease and modifiable host factors ▪ Assessment and correction of prosthesis design if required. Consider removal of prosthetic component for maintenance and cleaning. ▪ Maintenance visits for supra- and sub-gingival peri-implant cleaning. Ultrasonic scalers and manual debridement with metal/titanium tips. (3-6 months)

• Non-surgical management: ▪ Mechanical debridement of implant using manual or ultrasonic debridement with 2 weeks pre- and post-operative CHX 0.2% MW ▪ Consider adjunctive local antibiotics (minocycline/tetracycline)

• Surgical management (when resolution of peri-implantitis is not achieved with non- surgical treatment):

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▪ Open flap debridement with consideration of adjunctive therapy (laser, chlorhexidine, saline, air abrasion, hydrogen peroxide, EDTA) ▪ Regenerative approach: Xenograft with or without collagen membrane OR implantoplasty (modification of the implant surface topography) with apically repositioned flap

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6.1 Management of peri-implantitis: Algorithm for maintenance.

The following algorithms for the management of peri-implantitis have been devised by the author of this review based on the included studies and the studies presented in the literature review.

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6.2 Management of peri-implantitis: Summary algorithm for therapy.

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6.3 Management of peri-implantitis: Algorithm for non-surgical therapy.

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6.4 Management of peri-implantitis: Algorithm for surgical therapy.

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Appendices

Appendix 1

Protocol for systematic review:

Title: The professional management of peri-implantitis- a systematic review.

Focus question:

A number of systematic reviews have already addressed the topic of peri-implantitis management (Kotsovilis et al., 2008; Muthukuru et al., 2012; Heitz-Mayfield and Mombelli, 2014; Mahato, Wu and Wang, 2016; Ramanauskaite and Tervonen, 2016) including a Cochrane review published in 2008 (Esposito et al., 2008). There is no absolute explanation regarding the effectiveness of surgical and non-surgical management of peri- implantitis. This systematic review aims to assess the effectiveness of the treatment for peri- implantitis.

Dissemination plans: This review will be submitted for University of Bristol dissertation project, and submitted for potential publication into a peer reviewed journal.

To inform treatment protocols/guidelines for the treatment of peri-implantitis.

Contact details: Dr Chloe Harrington-Taylor.

Organisation: University of Bristol

Review team: Dr Chloe Harrington-Taylor

Costs: Approximately 600 hours of study time.

Anticipated start date: September 2016.

Anticipated completion date: June 2018.

Conflicts of interest: None.

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Language: English.

Country: United Kingdom.

Aims:

The primary aim of this review is to systematically appraise the available literature to evaluate the effectiveness of treatments for peri-implantitis in patients with functional osseointegrated dental implants. The review will serve to assess whether the literature currently available can provide sufficient data as to inform clinicians on how to manage peri-implantitis. If sufficient evidence is available, the secondary aim is to then provide clinical guidelines for treatment in line with the available literature.

Objectives:

In order to fulfil the aims of this review the following objectives will be set:

• Appraise the available literature for study design quality and bias. • To analyse qualitative data extracted from the available studies. • To analyse quantitative data extracted from the available studies. • Describe the treatment of peri-implantitis.

Review question:

“To assess the effectiveness of the currently available treatments for peri-implantitis”.

The review question was developed according to the population, intervention, comparison, and outcome (PICO) study design (See table 9).

Table 9 uses the PICO model to help define the search strategy for the studies focus question. The concept of PICO was introduced by (Richardson et al., 1995) to help specify a clinical question.

PICO Summary:

Population: Patients diagnosed with peri-implantitis

Intervention/exposure: Treatment for peri-implantitis (Surgical and non-surgical).

Comparison: As there is no defined standard of care for peri-implantitis any treatment used in a randomised controlled trial was used:

• comparison of different non-surgical interventions 130

• adjunctive treatments to non-surgical interventions • comparison of different surgical interventions • adjunctive treatments to surgical interventions.

Outcomes: Resolution of peri-implantitis

Primary outcomes:

• Implant failure • Complications and side effects. • Recurrence of peri-implantitis.

Secondary outcomes:

• % Bleeding on probing (BOP) sites • Clinical attachment level (CAL) change • Gingival margin recession • Peri-implant probing/ pocket depth (PPD/PD) • Radiographic bone level/bone loss (RBL/BL) • Implant mobility and RFA values •

Methods: Search Methods:

The methods including: search terms and Boolean operator algorithms, inclusion/exclusion criteria and limits were determined from initial scoping searches.

This systematic review will be performed independently by the author of this systematic review following the PRISMA guidelines for identification, screening, eligibility, and inclusion (Moher et al., 2009).

The systematic search strategy will be developed with guidance from the ‘Cochrane Handbook for Systematic Reviews of Interventions’ (Higgins and Green, 2008) and PRISMA guidelines (Liberati, 2009). The strategy will involve searches though electronic databases as well as hand searches.

Highly sensitive search strategies will be developed for each electronic database to maximise the retrieval of relevant records. The search strategies will be included a combination of search terms and Boolean operators. Each search strategy will be based on the search strategy developed for Medline and will be revised appropriately for each database.

Appendix 2-5 shows the search strategies developed for each database. It demonstrates the searched Keywords and Medical Subject Heading (MeSH) as well as the use of truncation and Boolean operators ‘AND’ and ‘OR’ to enhance each search.

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Each search strategy was developed from the Cochrane high sensitive search strategy (CHSSS) for identifying randomised controlled trials on Medline.

Data will be extracted from: • Central Medline via Ovid • Embase via Ovid • The Cochrane central register of controlled trials • Web of science

Hand searching:

Hand searching will include several dental journals as well as the bibliographies of the identified randomised controlled trials selected for full-text review. Hand searching has been recommended for systematic reviewers searching in order to minimize bias (Vassar, Atakpo and Kash, 2016). Hand searching of all references of full text articles will also be performed.

The following peer reviewed journals will be searched manually:

Hand searched journals:

Journal title

British Journal of Oral and Maxillofacial Surgery

Clinical Implant Dentistry and Related Research

Implant Dentistry

International Journal of Oral and Maxillofacial Surgery

International Journal of Periodontics and Restorative Dentistry

Journal of Dental Research

Journal of Oral Implantology

Journal of Oral and Maxillofacial Surgery

Clinical Oral Implants Research

The International Journal of Oral and Maxillofacial Implants

Journal of Periodontology

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Journal of Clinical Periodontology

European Journal of Oral Implantology

The Journal of Prosthetic Dentistry

The International Journal of Prosthodontics

Duplicates: Duplicates will be removed.

The articles will be subjected to a clear inclusion and exclusion criteria by a single reviewer (author).

Unpublished studies: No unpublished studies will be included in this review.

Selection of studies: Titles and abstracts derived from the systematic search will be independently screened by a single reviewer (author). All duplicates will be removed. The articles will be subjected to a clear inclusion and exclusion criteria.

Full texts of the studies meeting the inclusion criteria will be reviewed for eligibility and data extraction. Studies rejected at this or subsequent stages will be recorded in a table of excluded studies and the reasons for exclusion documented.

Study selection- Inclusion:

To be eligible for inclusion in this review, the study must:

• Be a randomised controlled trial • Describe a clinical intervention designed for the treatment of a condition compatible with the definition of peri-implantitis according to the latest definition of the American Academy of Periodontology, 2013 (American Academy of Periodontology, 2013) and the consensus from the Eighth European Workshop (Sanz and Chapple, 2012). Primary outcome*Probing depths>4mm Bone loss >/=2mm. • Include at least 10 participants with a follow up of 6 months minimum. • Include adult patients with at least one dental osseointegrated implant in function. • Clinical and/or radiographic changes reported. • Published in the last 10 years January 2007-September 2017.

The randomised comparative studies may include:

• non-surgical versus surgical interventions

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• comparison of different non-surgical interventions (+/- adjunctive therapy) • comparison of different surgical interventions (+/- adjunctive therapy)

Study selection -Exclusion: • Case reports and case studies • Systematic reviews, meta-analysis and literature reviews • Animal studies • In vivo studies

Data extraction: The identified studies will be appraised and data will be extracted and organised into tables.

The following data will be extracted and recorded: Title, authors, year of publication, country of origin, study design, number of participants, demographic details of participants, disease definition, intervention(s), follow up duration, outcomes recorded, results.

A narrative synthesis/appraisal of the included studies will be prepared.

Unclear or missing information or data: If required, an attempt will be made to contact the corresponding authors for obtaining missing, unclear or unpublished data.

Risk of bias/quality assessment: Quality assessment and assessment of risk of bias will be undertaken by the author as part of the data extraction process. The quality of each included article will be assessed using the Cochrane quality assessment tool (Higgins and Green, 2008). This 2-part tool was used to assess bias across the studies also. The Cochrane quality assessment tool focuses on six specific domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and 'other issues'). The information recorded during this assessment will be recorded in a table. Each included study will be given an overall risk of bias (Higgins and Green, 2008).

Each article will be critically appraised according to the critical appraisal skills programme PRISMA 2009 checklist.

Statistical analysis:

For dichotomous outcomes, the estimate of the effect of an intervention will be expressed as risk ratios (RR) together with 95% confidence intervals (CIs) displayed on forrest plots using Revman data program.

For continuous outcomes, mean differences and standard deviations will be expressed using mean differences and 95% Cis displayed on forrest plots using Revman data program.

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Meta-analyses will be performed if there were studies with similar comparisons reporting the same outcome measures- it is anticipated that there is likely to be heterogeneity between studies, thus, meta-analysis may not be possible.

Appendix 2

MEDLINE (OVID) search strategy: MEDLINE is the United States National Library of Medicine® database. It contains more than 22 million references to journal articles from 1946 onwards. MEDLINE was searched via the Ovid online platform. (peri-implant.Ovid.com)

This search was run with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: Sensitivity and precision maximising version (2008 revision) (Higgins and Green, 2008).

1. randomised controlled trial.pt. 2. controlled clinical trial.pt. 3. randomised.ab. 4. placebo.ab. 5. clinical trials as topic.sh 6. randomly.ab. 7. trial.ab. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. Peri-Implantitis/ 10. peri-implantitis or peri-implantitis or "peri implantitis" 11. 9 or 10 12. 8 and 11

Limit to English and 2006-current.

Ovid Medline search results:

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Appendix 3

MEDLINE in Progress search strategy This database includes records for new publications that will go into Medline but have not yet been fully indexed.

1. random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (double$ add blind$) or (single$ ad blind$) or assign$ or allocat$ or volunteer$ 2. peri-implantitis or peri-implantitis or "peri implantitis" 3. 1 OR 2

Search results for Medline in progress

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Appendix 4

EMBASE database search strategy: Embase was launched by Elsevier in 1974. It contains more than 29 million references from 1974 onwards. Embase Classic is a separate database that covers journals between 1947 and 1973. In this review, Embase was searched via the Ovid online platform.

(peri-implant.Ovid.com)

1. random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$ or allocat$ or volunteer$ 2. crossover procedure/ 3. double blind procedure/ 4. randomised controlled trial/ 5. single blind procedure/ 6. 1 or 2 or 3 or 4 or 5 7. Peri-Implantitis/ 8. peri-implantitis or peri-implantitis or "peri implantitis" 9. 7 or 8 10. 9 AND 6

Embase search results:

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Appendix 5

Cochrane Oral Health Group’s Trials Register search strategy

(dental-implants OR “dental implant*” OR “oral implant*” OR dental-implantation OR dental-prosthesis-implant-supported OR “implant supported” OR “implant supported prosthesis” OR dental-implantation- endosseous-endodontic OR “endosseous implant*” OR blade-implantation OR “blade implant*” OR (implant* AND (oral OR dental)) or dental-implantation-subperiosteal OR “sub- periosteal implant” OR (implant* AND overdenture*) OR ((overdenture* OR crown* OR bridge* OR prosthesis OR prostheses OR restoration*) AND (“dental implant*” OR “Oral implant” OR (zygoma* AND implant*))))

Search results:

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Appendix 6

Diagnostic criteria for diagnosis of peri-implantitis:

Currently there is no single uniform definition of peri-implantitis or the parameters that should be used to determine diagnosis (Ramanauskaite and Juodzbalys, 2016). An electronic literature search was conducted of the MEDLINE (Ovid) and EMBASE databases for articles/ systematic reviews/guidelines or consensus statements looking at diagnostic parameters for peri-implantitis. The databases were searched for articles in English language published between 2000 and 2017. Sequential screening at the title/abstract was performed.

Search: “Peri-implantitis or Peri-implantitis or peri-implantitis AND Definition or classification.

The diagnostic criteria of peri-implantitis described across some of the studies was extracted and is presented in the table below:

According to the latest definition of the American Academy of Periodontology, 2013 (American Academy of Periodontology, 2013) and the consensus from the Eighth European Workshop (Sanz and Chapple, 2012). A peri-implant probing depth (PIPD) >/=4mm, with progressive loss of supporting bone beyond biological bone remodelling >/=2mm. As well as bleeding on probing (BOP) and the presence of suppuration SUP) indicates peri- implantitis. This definition is the most consistently reported across the studies included in Table 25.

For the purpose of this systematic review studies will be included if they describe a pathological condition of peri-implantitis with bone loss>/=4mm with bone loss >/=2mm.

Table 31: to summarise the diagnostic criteria for the diagnosis of peri-implantitis following a literature search.

PIPD Author and year BOP Suppuration Bone loss (mm) (mm) Zetterqvist et al., 2010 + + >5 >5

Wahlström, Sagulin and >/=2mm Jansson, 2010 + + ?

Padial-Molina et al., PD > 6 mm 2014 + + bone loss ≥ 2 mm

Ata-Ali, Ata-Ali and + + ? Stage I: < 3 mm beyond biological bone 139

Bagan, 2015 remodeling. Stage II: > 3 mm but < 5 mm beyond biological bone remodeling. Stage III: ≥ 5 mm Stage IV: ≥ 50% of the implant length Misch et al., 2008 > 4 mm, < 1/2 implant body +/- +/- >7

Always accompanied by loss of supporting Lindhe and Meyle, Deepened + + marginal bone. 2008 pockets

Froum and Rosen, 2012 Early ≥ 4 <25% of implant length Moderate ≥ 25-50% of implant length + + 6 >50% of implant length Advanced ≥

8 Dvorak et al., 2011 + + >5mm Bone loss beyond expected remodeling. Lopez-Piriz et al., 2012 + + ? >/=3mm Roccuzzo et al., 2011 + + >4 >/=2mm Mir-Mari et al., 2012 + + >5mm >/= 2 threads Cecchinato, Parpaiola + + >/=4mm >0.5mm and Lindhe, 2012 Canullo et al., 2015 + + 3-5mm >3mm Charalampakis et al., + + >/=5 >/=1.8mm 2011 Ravald et al., 2012 + + >4 >/2mm Stoker, van Waas and + + >5 >/=3 Wismeijer, 2011 Marrone et al., 2012 + + >4 >/=2mm Gotfredsen, 2009 + + >/=5 >/=2mm > 5 mm Heitz-Mayfield, 2008 + + Circumferential bone loss.

Salvi et al., 2007 + + ≥ 5 mm, ≥ 2 mm, Persson et al., 2006 + + ≥ 5 mm, ≥ 2 mm, Renvert et al., 2006 + + >/=5mm >3mm Renvert et al., 2008 + + >/=5mm >3mm Persson et al., 2011 + + >/=5mm 3mm Froum, Froum and + + >/=6mm >/=2mm Rosen, 2015 Schwarz et al., 2010 + + >6 >3 Heitz-Mayfield et al., + + >/=5mm >/=2 2011

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Appendix 7

Risk of bias tables with authors judgment and support for judgement.

Table 32: Carcuac et al., 2015: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence generation Low risk Computer generated randomisation (selection bias) procedure. Stratified for smokers and non- smokers. Allocation concealment Unclear risk Sample size calculation completed. (selection bias) Blinding of participants and Unclear risk Not described personnel (performance bias) Blinding of outcome Unclear risk Not described assessment (detection bias) Incomplete outcome data High risk Incomplete entries.11 subjects lost to follow (attrition bias) up. 6 implants removed during the study (6 patients). Selective reporting (reporting High risk 6 patients had failed implants. 1 implant per bias) patient. Other bias Unclear risk None apparent.

Table 33: de Waal et al., 2012: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence generation Unclear risk Randomly allocated to placebo or test group. (selection bias) Computer generated randomisation. Allocation concealment Low risk Double blinding. Sample size calculation (selection bias) carried out. Blinding of participants and Low risk Double blinding investigators and subjects. personnel (performance bias) Blinding of outcome Unclear risk Double blinding assessment (detection bias) Incomplete outcome data High risk 3 subjects from placebo group discontinued (attrition bias) study. Implants removed due to failure. Selective reporting (reporting Unclear risk 10 implants not included in final reporting bias) due to loss (3 subjects) multiple implants per patient. Other bias Unclear risk Multiple implants per patient.

141

Table 34: de Waal et al., 2014: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection Randomised using a one to one allocation ratio. bias) Sequentially numbered envelopes.

Allocation Low risk concealment Double blinding (selection bias) Blinding of Low risk participants and Double blinding. personnel (performance bias) Blinding of outcome Low risk assessment (detection Double blinding bias) Incomplete outcome Unclear risk 5 implants (3 subjects) from control group data (attrition bias) discontinued intervention- due to persisting peri- implantitis. 1 implant (1 subject) discontinued due to fractured implant. All reasons for discontinuing recorded. Selective reporting Unclear risk Analysis performed for intention to treat. Multiple (reporting bias) implants per patient considered. Other bias Unclear risk Multiple implants per patient considered.

Table 35: Esposito et al., 2013: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection Random sequence generation bias)

Allocation concealment Unclear risk Computer generated restricted lists Only one (selection bias) investigator had access to the randomisation lists. Blinding of participants Unclear risk Treatment allocations were concealed to the and personnel investigators. (performance bias) Blinding of outcome Low risk At each centre, there was a locally blinded assessment (detection outcome assessor who recorded all of the outcome bias) measures. The assessors were not calibrated. Incomplete outcome data Unclear risk At 1 year 3 patients dropped out. Reasons (attrition bias) recorded. 142

Selective reporting Unclear risk None apparent. (reporting bias) Other bias Low risk This study was sponsored by Fotosan. However, sponsorship was removed when no differences between the control and the test were detected.

Table 36: Javed et al., 2016: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence generation Low risk Randomisation procedure carried (selection bias) out by coin toss. Allocation concealment (selection Unclear risk Unclear bias) Blinding of participants and personnel Unclear risk Unclear (performance bias) Blinding of outcome assessment Low risk Single blinded and calibrated (detection bias) investigator. Incomplete outcome data (attrition Low risk No drop outs. All subjects bias) completed the study. Selective reporting (reporting bias) Low risk All data reported. Other bias Unclear risk None apparent.

Table 37: Machtei et al., 2012: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection Computer generated randomisation. bias)

Allocation concealment Low risk Double blinded. (selection bias) Blinding of participants Low risk and personnel Double blinded multicentre study (performance bias) Blinding of outcome Low risk Double blinding. 2 separate examiners: 1 for assessment (detection treatment one for examination. bias) Incomplete outcome High risk 4 subjects lost to follow up. 2 patients’ reasons are data (attrition bias) clear. 2 subjects were withdrawn, due to emergency dental treatment which interfered with the study endpoint. 143

Selective reporting High risk 2 subjects were withdrawn, due to emergency (reporting bias) dental treatment which interfered with the study endpoint. Other bias Unclear risk Multiple implants per patient. No more than 2 implants per patient.

Table 38: Papadopoulos et al., 2015: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence generation (selection Low risk Computer generated bias) randomisation Allocation concealment (selection bias) Unclear risk Unclear Blinding of participants and personnel Unclear risk Unclear (performance bias) Blinding of outcome assessment (detection Low risk Blinded outcome assessor bias) Incomplete outcome data (attrition bias) Low risk All reported Selective reporting (reporting bias) Low risk All reported Other bias Unclear risk None apparent.

Table 39: Persson et al., 2010: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection bias) Computer generated randomisation procedure

Allocation concealment Unclear risk Unclear (selection bias) Blinding of participants Low risk Subjects were requested not to discuss the and personnel therapy with the examiner. (performance bias) Blinding of outcome Unclear risk Single blinding, examiner blinded. assessment (detection bias) Incomplete outcome data Low risk Ultrasonic group: 2 subjects lost to follow up in (attrition bias) group 1, 4 subjects in group 2 lost to follow up. All data reported. Selective reporting Unclear risk Patient level data not reported in tables. Only (reporting bias) microbiological outcomes. Other bias Low risk None apparent.

144

Table 40: Renvert et al., 2011: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence generation Low risk Computer generated randomisation (selection bias) procedure. Computer generated randomisation procedure. Allocation concealment Unclear risk Single masked procedure- study examiner. (selection bias) Blinding of participants and Low risk Study subjects were instructed not to discuss personnel (performance bias) the therapy with the study examiner. Blinding of outcome Low risk Examiner- blinded assessment (detection bias) Incomplete outcome data Low risk All subjects completed the study. No drop (attrition bias) outs or withdrawals. Selective reporting (reporting Unclear risk All subjects completed the study. No drop bias) outs or withdrawals. Data at patient level not reported. Other bias Unclear risk Multiple implants considered per patient. 46 subjects (100 implants).

Table 41: Schwarz et al., 2007: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection bias) Computer generated randomisation procedure.

Allocation concealment Unclear risk Unclear. (selection bias) Blinding of participants Low risk and personnel Blinded and calibrated investigator. (performance bias) Blinding of outcome Low risk assessment (detection Single blinded investigator. bias) Incomplete outcome data High risk At 12 months 2 subjects from the test group (2 (attrition bias) implants) were excluded from the study due to severe pus formation. Data not presented. Selective reporting High risk Data from excluded subjects not completed. (reporting bias) Incomplete reporting for 2 subjects 92 implants). No withdrawals or drop outs. Other bias Low risk None apparent.

145

Table 42: Schwarz et al., 2011: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection Computer generated randomisation procedure. bias) Power calculation to determine sample size.

Allocation concealment Unclear risk Unclear (selection bias) Blinding of participants Low risk and personnel Single blinding. Blinded and calibrated investigator. (performance bias) Blinding of outcome Low risk assessment (detection Blinded outcome assessor. bias) Incomplete outcome Unclear risk CPS group. 1 subject lost to follow up at 2 months. data (attrition bias) ERL group. 1 subject lost to follow up at 3 months. Reasons for drop out described. Selective reporting High risk Data not reported for patients who were removed (reporting bias) from study and received retreatment. retreatment data not presented. No bone level data displayed but described in methodology. Other bias Unclear risk Study received sponsorship from biomaterials company. No apparent bias detected.

Table 43: Schwarz et al., 2012: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection bias) Computer generated randomisation procedure.

Allocation concealment Unclear risk Unclear (selection bias) Blinding of participants and Unclear risk personnel (performance Unclear if subjects are blinded bias) Blinding of outcome Low risk Outcome recorded by single blinded calibrated assessment (detection bias) investigator. Incomplete outcome data Unclear risk CPS group: 1 subject (1 implant) lost at 2 (attrition bias) months 1 implant *1 subject lost at 6-24 months. ERL group. 1 subject lost to follow up at 3 months. 5 lost to follow up at 6-24 months. 146

Reasons for drop out described. n=8 subjects failed to attend follow up appointments and were therefore excluded. Selective reporting High risk Reasons for drop out described. Data not (reporting bias) reported for excluded patients Other bias Low risk None apparent

Table 44: Schwarz et al., 2013: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence Low risk generation (selection Computer generated randomisation procedure bias)

Allocation Unclear risk concealment Unclear. (selection bias) Blinding of Unclear risk participants and Unclear if subjects are blinded. Single blinded personnel calibrated examiner. (performance bias) Blinding of outcome Low risk assessment Single blinded calibrated examiner. (detection bias) Incomplete outcome High risk CPS group: 4 patients lost 2-48 months. data (attrition bias) ERL group: 7 subjects lost 2-48 months. Reasons described. 11 subjects failed to attend follow up appointments. 4 patients were excluded from the study between 24-36 months due to severe signs of reinfection- the patients were provided with retreatment but the retreatment outcome data is not reported. Selective reporting High risk 4 patients were excluded from the study between 24-36 (reporting bias) months due to severe signs of reinfection- the patients were provided with retreatment but the retreatment outcome data is not reported. No bone level data reported? Other bias Unclear risk Multiple implants considered per patient.

147

Table 45: Wohlfahrt et al., 2012: Risk of bias table. Authors' Bias Support for judgement judgement

Random sequence generation (selection Low risk Random assignment of bias) subjects to groups. Allocation concealment (selection bias) Unclear risk Unclear Blinding of participants and personnel Low risk Blinded examiner (performance bias) Blinding of outcome assessment Low risk Blinded examiner (detection bias) Incomplete outcome data (attrition bias) Low risk All data reported Selective reporting (reporting bias) Low risk All data reported Other bias Unclear risk None apparent.

148

Appendix 8

References for excluded studies

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Arisan V; Karabuda ZC; Arici SV; Topcuoglu N; Kulekci G. (2015) A randomised clinical trial of an adjunct diode laser application for the non-surgical treatment of peri-implantitis. Photomedicine and Laser Surgery 33(11):547-54.

Sahm N; Becker J; Schwarz F. Clinical Oral Investigations. (2015). Non-surgical treatment of peri-implantitis using an air-abrasive device or mechanical debridement and local application of chlorhexidine. Twelve-month follow-up of a prospective, randomised, controlled clinical study. 19(8):1807-14.

Bassetti M; Schar D; Wicki B; Eick S; Ramseier CA; Arweiler NB; Sculean A; Salvi GE. (2014). Anti-infective therapy of peri-implantitis with adjunctive local drug delivery or photodynamic therapy: 12-month outcomes of a randomised controlled clinical trial. Clinical Oral Implants Research. 25(3):279-87.

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Schwarz F; Bieling K; Nuesry E; Sculean A; Becker J. (2006) Clinical and histological healing pattern of peri-implantitis lesions following non-surgical treatment with an Er:YAG laser. Lasers in Surgery & Medicine. 38(7):663-71.

Schar D; Ramseier CA; Eick S; Arweiler NB; Sculean A; Salvi GE (2103). Anti-infective therapy of peri-implantitis with adjunctive local drug delivery or photodynamic therapy: six-month outcomes of a prospective randomised clinical trial. Clinical Oral Implants Research. 24(1):104-10.

De Angelis N; Felice P; Grusovin MG; Camurati A; Esposito M (2012). The effectiveness of adjunctive light-activated disinfection (LAD) in the treatment of peri-implantitis: 4- month results from a multicentre pragmatic randomised controlled trial. European Journal of Oral Implantology. 5(4):321-31.

Romeo E; Lops D; Chiapasco M; Ghisolfi M; Vogel G (2007). Therapy of peri-implantitis with resective surgery. A 3-year clinical trial on rough screw-shaped oral implants. Part II: radiographic outcome. Clinical Oral Implants Research. 18(2):179-87. 149

Renvert S; Lessem J; Dahlen G; Renvert; Lindahl C (2008). Mechanical and repeated antimicrobial therapy using a local drug delivery system in the treatment of peri-implantitis: a randomised clinical trial. Journal of Periodontology. 79(5):836-44.

Renvert S; Samuelsson E; Lindahl C; Persson GR (2009). Mechanical non-surgical treatment of peri-implantitis: a double-blind randomised longitudinal clinical study. I: clinical results. Journal of Clinical Periodontology. 36(7):604-9.

Roos-Jansåker, A, Almhöjd, U. and Jansson, (2015). Treatment of peri-implantitis: clinical outcome of chloramine as an adjunctive to non-surgical therapy, a randomised clinical trial. Clinical Oral Implants Research, 28(1), pp.43-48.

Karimi, M, Hasani, A. and Khosroshahian, S. (2016). Efficacy of Antimicrobial Photodynamic Therapy as an Adjunctive to Mechanical Debridement in the Treatment of Peri-implant Diseases: A Randomised Controlled Clinical Trial. Journal of Lasers in Medical Sciences, 7(3), pp.139-145.

Romeo, U, Nardi, G, Libotte, F, Sabatini, S, Palaia, G. and Grassi, F. (2016). The Antimicrobial Photodynamic Therapy in the Treatment of Peri-Implantitis. International Journal of Dentistry, 2016, pp.1-5.

Hentenaar, D, De Waal, Strooker, Meijer, Van Winkelhoff, A. and Raghoebar, G. (2017). Implant decontamination with phosphoric acid during surgical peri-implantitis treatment: a RCT. International Journal of Implant Dentistry, 3(1).

Hamzacebi, B, Oduncuoglu, B. and Alaaddinoglu, E. (2015). Treatment of Peri-implant Bone Defects with Platelet-Rich Fibrin. The International Journal of Periodontics & Restorative Dentistry, 35(3), pp.415-422.

Arısan, V, Karabuda, Z, Arıcı, S, Topçuoğlu, N. and Külekçi, G. (2015). A Randomised Clinical Trial of an Adjunct Diode Laser Application for the Non-Surgical Treatment of Peri-Implantitis. Photomedicine and Laser Surgery, 33(11), pp.547-554.

Renvert, S, Lessem, J, Dahlen, G, Lindahl, C. and Svensson, M. (2006). Topical minocycline microspheres versus topical chlorhexidine gel as an adjunct to mechanical debridement of incipient peri-implant infections: a randomised clinical trial. Journal of Clinical Periodontology, 33(5), pp.362-369.

Büchter, A, Meyer, U, Kruse-Lösler, B, Joos, U. and Kleinheinz, J. (2004). Sustained release of doxycycline for the treatment of peri-implantitis: randomised controlled trial. British Journal of Oral and Maxillofacial Surgery, 42(5), pp.439-444.

Tang Z; Cao C; Sha; Lin; Wang X. Chung-Hua Kou Chiang i Hsueh Tsa Chih (2002). Effects of non-surgical treatment modalities on peri-implantitis. Chinese Journal of Stomatology. 37(3):173-5

Sahm N; Becker J; Santel T; Schwarz F (2011). Non-surgical treatment of peri-implantitis using an air-abrasive device or mechanical debridement and local application of 150

chlorhexidine: a prospective, randomised, controlled clinical study. Journal of Clinical Periodontology. 38(9):872-8

Bombeccari GP; Guzzi G; Gualini F; Gualini S; Santoro F; Spadari F (2013) Photodynamic therapy to treat peri-implantitis. Implant Dentistry. 22(6):631-8.

Renvert, S, Lessem, J, Dahlén, G, Renvert. and Lindahl, C. (2008). Mechanical and Repeated Antimicrobial Therapy Using a Local Drug Delivery System in the Treatment of Peri-Implantitis: A Randomised Clinical Trial. Journal of Periodontology, 79(5), pp.836- 844.

Persson, G, Samuelsson, E, Lindahl, C. and Renvert, S. (2010). Mechanical non-surgical treatment of peri-implantitis: a single-blinded randomised longitudinal clinical study. II. Microbiological results. Journal of Clinical Periodontology, 37(6), pp.563-573.

Gomi, K, Matsushima, , Ujiie, , Shirakawa, S, Nagano, T, Kanazashi, M. and Yashima, A. (2015). Full-mouth scaling and root planing combined with azithromycin to treat peri- implantitis. Australian Dental Journal, 60(4), pp.503-510.

Schär, D, Ramseier, C, Eick, S, Arweiler, N, Sculean, A. and Salvi, G. (2012). Anti- infective therapy of peri-implantitis with adjunctive local drug delivery or photodynamic therapy: six-month outcomes of a prospective randomised clinical trial. Clinical Oral Implants Research, 24(1), pp.104-110.

Bassetti, M, Schär, D, Wicki, B, Eick, S, Ramseier, C, Arweiler, N, Sculean, A. and Salvi, G. (2013). Anti-infective therapy of peri-implantitis with adjunctive local drug delivery or photodynamic therapy: 12-month outcomes of a randomised controlled clinical trial. Clinical Oral Implants Research, 25(3), pp.279-287.

Sahm, JGN, Becker, J. and Schwarz, F. (2015). Non-surgical treatment of peri-implantitis using an air-abrasive device or mechanical debridement and local application of chlorhexidine. Twelve-month follow-up of a prospective, randomised, controlled clinical study. Clinical Oral Investigations, 19(8), pp.1807-1814.

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