Periodontitis is one of the primary causes of tooth loss, and is also related to various systemic diseases. Early detection of this condition is crucial when it comes to preventing further oral damage and the associated health complications. This study offers a systematic review of the literature published up to April 2023, and aims to clearly explain the role of proteomics in identifying salivary biomarkers for periodontitis. Comprehensive searches were conducted on PubMed and Web of Science to shortlist pertinent studies. The inclusion criterion was those that reported on mass spectrometry-driven proteomic analyses of saliva samples from periodontitis cohorts, while those on gingivitis or other oral diseases were excluded. An assessment for risk of bias was carried out using the Newcastle–Ottawa Scale and Quality Assessment of Diagnostic Accuracy Studies or the NIH quality assessment tool, and a meta-analysis was performed for replicable candidate biomarkers, i.e., consistently reported candidate biomarkers (in specific saliva samples, and periodontitis subgroups, reported in ≥2 independent cohorts/reports) were identified. A Gene Ontology enrichment analysis was conducted using the Database for Annotation, Visualization, and Integrated Discovery bioinformatics resources, which consistently expressed candidate biomarkers, to explore the predominant pathway wherein salivary biomarkers consistently manifested. Of the 15 studies included, 13 were case–control studies targeting diagnostic biomarkers for periodontitis participants (periodontally healthy/diseased, n = 342/432), while two focused on biomarkers responsive to periodontal treatment (n = 26 participants). The case–control studies were considered to have a low risk of bias, while the periodontitis treatment studies were deemed fair. Summary estimate and confidence/credible interval, etc. determination for the identified putative salivary biomarkers could not be ascertained due to the low number of studies in each case. The results from the included case–control studies identified nine consistently expressed candidate biomarkers (from nine studies with 230/297 periodontally healthy/diseased participants): (i) those that were upregulated: alpha-amylase, serum albumin, complement C3, neutrophil defensin, profilin-1, and S100-P; and (ii) those that were downregulated: carbonic anhydrase 6, immunoglobulin J chain, and lactoferrin. All putative biomarkers exhibited consistent regulation patterns. The implications of the current putative marker proteins identified were reviewed, with a focus on their potential roles in periodontitis diagnosis and pathogenesis, and as putative therapeutic targets. Although in its early stages, mass spectrometry-based salivary periodontal disease biomarker proteomics detection appeared promising. More mass spectrometry-based proteomics studies, with or without the aid of already available clinical biochemical approaches, are warranted to aid the discovery, identification, and validation of periodontal health/disease indicator molecule(s). Protocol registration number: CRD42023447722; supported by RD-02-202410 and GRF17119917.
