Peri-Implantitis Causal Therapy with and Without Doxycycline: Retrospective Cohort Clinical Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

After critically reviewing this Research Article titled "Peri-implantitis causal therapy with and without doxycycline: retrospective cohort clinical study", I detected some MINOR flaws, which determined my recommendation of “ACCEPT UNDER REVIEW”. Below please find my detailed comments.

The authors carried out a retrospective cohort clinical study on the causal therapy of peri-implantitis with and without doxycycline, associating it with factors such as smoking, systemic problems and types of implant rehabilitation.

The study is well written and conducted, methodology applied is very appropriate and quite detailed and well described in the paper, with minor flaws and easily corrected and appropriate for the objectives of the work. Statistical analyzes of the results obtained were well conducted.

The results obtained were promising and the discussions were relevant to the results achieved.

Below are my comments:

• Abstract: Authors should better define the size of the sample that was analyzed in the abstract, number of individuals in the control group and in the test group, as described in Table 1.
• As topical doxycycline is not available in all parts of the world, I suggest that a paragraph be added explaining its mechanism of action in more detail in the introduction, how this formulation acts within the periodontal pocket, how long the action lasts, whether it is microencapsulated or another methodology is used to ensure its prolonged action.
• Table 1 has the row numbers above it, it must be a formatting error
• In this reviewer's opinion, the results would be better visualized if placed in graphs, as the continuous text ends up confusing the general parameter of the clinical situation a little.

The conclusions of the article are consistent with the results obtained, where the authors describe the limitations and are fair with their clinical findings.

Author Response

Dear Reviewer,
Thank you for your valuable suggestions which we sincerely hope have helped to improve the paper and make it suitable for acceptance in your journal.
We remain at your disposal for any further clarifications. 
Best regards

After critically reviewing this Research Article titled "Peri-implantitis causal therapy with and without doxycycline: retrospective cohort clinical study", I detected some MINOR flaws, which determined my recommendation of “ACCEPT UNDER REVIEW”. Below please find my detailed comments.
The authors carried out a retrospective cohort clinical study on the causal therapy of peri-implantitis with and without doxycycline, associating it with factors such as smoking, systemic problems and types of implant rehabilitation.
The study is well written and conducted, methodology applied is very appropriate and quite detailed and well described in the paper, with minor flaws and easily corrected and appropriate for the objectives of the work. Statistical analyzes of the results obtained were well conducted.
The results obtained were promising and the discussions were relevant to the results achieved.
Below are my comments:
•    Abstract: Authors should better define the size of the sample that was analyzed in the abstract, number of individuals in the control group and in the test group, as described in Table 1.

The abstract was modified as follows.

Background: Topical application within peri-implant pockets ensures high drug concentrations at the infection site while minimizing systemic exposure. However, the comparative effectiveness of non-surgical causal therapy alone versus its combination with doxycycline remains unclear. This retrospective observational clinical study aimed to evaluate the impact of adjunctive doxycycline on peri-implant parameters, considering smoking, systemic conditions, and implant-prosthetic rehabilitation (single implant, implant-supported bridge, or full-arch). Methods: Patients were retrospectively assigned to a Control Group (CG), receiving non-surgical causal therapy alone, or a Test Group (TG), treated also with topical doxycycline. Peri-implant parameters, including Peri-implant Probing Depht (PPD), Bleeding on Probing (BoP), Plaque Index (PI), and suppuration, were assessed at baseline (T0) and follow-up (T1). Multivariate logistic regression and stratified subgroup analyses were conducted to adjust for confounders such as smoking, systemic conditions, and implant-prosthetic rehabilitation type. Results: 209 patients were included in the study, of whom 97 in CG and 112 in TG. At T1, TG exhibited a statistically significant reduction in PPD, BoP, PI, and suppuration compared to CG (p < 0.05). Conclusions: The adjunctive use of topical doxycycline significantly enhances clinical outcomes in non-surgical peri-implantitis treatment. Further longitudinal studies are needed to confirm these findings and assess long-term stability.

•    As topical doxycycline is not available in all parts of the world, I suggest that a paragraph be added explaining its mechanism of action in more detail in the introduction, how this formulation acts within the periodontal pocket, how long the action lasts, whether it is microencapsulated or another methodology is used to ensure its prolonged action.
We added the following paragraph in the introduction section:

Such topical formulations, particularly doxycycline, are often delivered in the form of bioabsorbable gels or microencapsulated microspheres that provide sustained release of the active ingredient for a period generally ranging from 7 to 14 days. After application at the infected site, doxycycline reaches high local concentrations, exceeding the minimum inhibitory concentration (MIC) for the main periodontal and peri-implant pathogens. The mechanism of action is based on inhibition of bacterial protein synthesis through binding to the 30S ribosomal subunit. In addition, doxycycline also possesses documented anti-inflammatory properties, including inhibition of matrix metalloproteinases (MMPs), which contribute to the reduction of soft and hard tissue destruction. This dual effect, antibacterial and modulating the host response, makes topical formulations a valuable adjunct to non-surgical therapy in cases of incipient mucositis or peri-implantitis [25,26].

•    Table 1 has the row numbers above it, it must be a formatting error
It was removed. 

•    In this reviewer's opinion, the results would be better visualized if placed in graphs, as the continuous text ends up confusing the general parameter of the clinical situation a little.

Several graphs were added.

The conclusions of the article are consistent with the results obtained, where the authors describe the limitations and are fair with their clinical findings.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is well thought and written, but it needs some improvement

1. What type of implants were the patient inserted? Which type of threads, design of the implants, features which influence  the degree of peri-implantitis and bone loss? The same for the design and material of prosthesis - screwed or cemented? full ceramic or metalo-ceramic?
2. I saw no peri-implantitis staging in Results section, which is the underlying key of the study. Moreover, the classification might be adjusted to single-bridge-full mouth or systemic/clinical healthy patients.

 

Author Response

Dear Reviewer,
Thank you for your valuable suggestions which we sincerely hope have helped to improve the paper and make it suitable for acceptance in your journal.
We remain at your disposal for any further clarifications. 
Best regards

The manuscript is well thought and written, but it needs some improvement
1.    What type of implants were the patient inserted? Which type of threads, design of the implants, features which influence  the degree of peri-implantitis and bone loss? The same for the design and material of prosthesis - screwed or cemented? full ceramic or metalo-ceramic?
You are absolutely right. I added in inclusion criteria a parameter that we had considered when selecting patients but had not written down. We did not statistically evaluate the role of implant design on the occurrence of peri-implantitis because we were interested in the treatment response according to the parameters we considered in the study.
•    Subjected to exclusively screw-retained full-ceramic implant-prosthetic rehabilitation, regardless of implant design;

2.    I saw no peri-implantitis staging in Results section, which is the underlying key of the study. Moreover, the classification might be adjusted to single-bridge-full mouth or systemic/clinical healthy patients.
We thank the Reviewer for the thoughtful comment regarding the absence of peri-implantitis staging in the Results section. We acknowledge the relevance of disease staging in understanding clinical progression and tailoring treatment strategies.
In the present study, all included patients met the diagnostic criteria for peri-implantitis based on the 2018 Classification of Periodontal and Peri-Implant Diseases and Conditions (Chapple et al.). However, the statistical analysis was designed to investigate the effect of topical doxycycline as an adjunct to non-surgical treatment, with particular focus on how systemic conditions, smoking habits, and the type of implant-supported rehabilitation influenced the variation of peri-implant clinical parameters (PPD, BoP, PI, and suppuration) over time.
Although peri-implantitis staging was part of the diagnostic workup during patient selection, it was not included as a variable in the statistical analysis. This decision was made for methodological consistency and to maintain sufficient statistical power across stratified subgroups, given the retrospective design and predefined sample size. Additionally, because the aim was to evaluate clinical response to therapy in real-world patients with peri-implantitis rather than to explore correlations with disease severity, we focused the analysis on dynamic clinical changes and their relationship to patient-related and prosthetic factors.
Nevertheless, we recognize the value of peri-implantitis staging and will consider its inclusion in future studies with prospective design and larger sample sizes, where more detailed stratification can be performed without compromising statistical validity.

Reviewer 3 Report

Comments and Suggestions for Authors

I congratulate the authors for their hard work.

I have some recommendations:

1)Introduction

- I suggest first adding the hypothesis within the Introduction and then in the Discussion part.

2) Results

• I suggest inserting the following text (lines 351-353): "Overall, the results showed that TG achieved significant improvements in peri-implant parameters from time 0 to follow-up, regardless of systemic disease, smoking habit or type of implant-prosthetic rehabilitation." in the Conclusion part.

3) Conclusions

Please rephrase this part briefly and make it more understandable. Do not forget lines 351-353.

4) References

- please check and write them according to the Journal's recommendations.

Author Response

Dear Reviewer,
Thank you for your valuable suggestions which we sincerely hope have helped to improve the paper and make it suitable for acceptance in your journal.
We remain at your disposal for any further clarifications. 
Best regards

I congratulate the authors for their hard work.
I have some recommendations:
1)Introduction
- I suggest first adding the hypothesis within the Introduction and then in the Discussion part.
The null hypothesis was written in detail in the statistical analysis section because there were several co-variables considered and it was not possible to summarise without being summary in the introduction.
In the discussion all results were discussed and compared with the literature.

2) Results
•    I suggest inserting the following text (lines 351-353): "Overall, the results showed that TG achieved significant improvements in peri-implant parameters from time 0 to follow-up, regardless of systemic disease, smoking habit or type of implant-prosthetic rehabilitation." in the Conclusion part.
3) Conclusions
Please rephrase this part briefly and make it more understandable. Do not forget lines 351-353.

We remove the sentence from results and modified the conclusion as follows:
Within the limitations of this retrospective study, the adjunctive use of topical doxycycline in non-surgical peri-implantitis treatment resulted in significantly greater improvements in clinical parameters compared to mechanical therapy alone.
Overall, the results showed that the test group (TG) achieved significant improvements in peri-implant parameters from baseline to follow-up, regardless of systemic condition, smoking status, or type of implant-supported rehabilitation.
These findings support the clinical benefit of combining topical doxycycline with mechanical debridement in the management of peri-implant disease. Further prospective studies are needed to confirm these results and evaluate long-term outcomes.

4) References
- please check and write them according to the Journal's recommendations.
We checked. 

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Dear authors,

I wait for the next extended cohort study regarding doxycycline effect on periodontal disease.