Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis

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Rheumatoid arthritis (RA), a systemic autoimmune disease that has been associated with increased severity of periodontal disease. This study aimed to evaluate the salivary levels human leukocyte antigen-DR4 (HLA-DR4), matrix metalloproteinase-8 (MMP-8), and anti-citrullinated protein antibody (ACPA), and to assess their diagnostic potential using ROC curve analysis in periodontitis patients with and without rheumatoid arthritis. Methods The study included three groups; thirty patients with PD, thirty patients with PD and RA, and twenty healthy control participants. Clinical periodontal parameters [plaque Index (PLI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment loss (CAL)] were assessed. Salivary biomarkers were analyzed by enzyme-linked immunosorbent assay (ELISA), and the microbial load of Porphyromonas gingivalis (P. gingivalis) was determined using quantitative real time polymerase chain reaction (qRT-PCR). Results Our findings showed that salivary HLA-DR4 levels were significantly lower in patient groups compared with healthy controls (P = 0.000), whereas salivary MMP-8 and ACPA levels were significantly elevated in patients (P = 0.034) and (P = 0.001) respectively, with no significant differences between the patient groups(P > 0.05). On the other hand, microbial load was significantly higher in the PD with and without RA groups than that in controls (P = 0.001), with a positive correlation between microbial load and CAL in the PD-RA group. 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F1000Research 2025, 14 :615 ( https://doi.org/10.12688/f1000research.164552.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] Shaymaa Abdulkareem Nori https://orcid.org/0009-0003-3621-4094 1,2 , Batool Hassan Al-Ghurabi 1 , Nik Nairan Abdullah 3 Shaymaa Abdulkareem Nori https://orcid.org/0009-0003-3621-4094 1,2 , Batool Hassan Al-Ghurabi 1 , Nik Nairan Abdullah 3 PUBLISHED 30 Oct 2025 Author details Author details 1 Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Baghdad Governorate, Iraq 2 Department of Prosthodontics, College of Dentistry, Al-Hadi University, Baghdad, Baghdad Governorate, Iraq 3 Department Public Health Medicine, Faculty Medicine, Universiti Teknologi, Sungai Buloh Campus, Selangor, Malaysia Shaymaa Abdulkareem Nori Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Batool Hassan Al-Ghurabi Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Software, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Nik Nairan Abdullah Roles: Data Curation, Formal Analysis, Methodology, Project Administration, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Pathogens gateway. Abstract Background Periodontitis (PD) is a chronic infectious inflammatory disease that affects the tissues supporting teeth and results in a progressive deterioration of the alveolar bone. Rheumatoid arthritis (RA), a systemic autoimmune disease that has been associated with increased severity of periodontal disease. This study aimed to evaluate the salivary levels human leukocyte antigen-DR4 (HLA-DR4), matrix metalloproteinase-8 (MMP-8), and anti-citrullinated protein antibody (ACPA), and to assess their diagnostic potential using ROC curve analysis in periodontitis patients with and without rheumatoid arthritis. Methods The study included three groups; thirty patients with PD, thirty patients with PD and RA, and twenty healthy control participants. Clinical periodontal parameters [plaque Index (PLI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment loss (CAL)] were assessed. Salivary biomarkers were analyzed by enzyme-linked immunosorbent assay (ELISA), and the microbial load of Porphyromonas gingivalis ( P. gingivalis ) was determined using quantitative real time polymerase chain reaction (qRT-PCR). Results Our findings showed that salivary HLA-DR4 levels were significantly lower in patient groups compared with healthy controls (P = 0.000), whereas salivary MMP-8 and ACPA levels were significantly elevated in patients (P = 0.034) and (P = 0.001) respectively, with no significant differences between the patient groups(P > 0.05). On the other hand, microbial load was significantly higher in the PD with and without RA groups than that in controls (P = 0.001), with a positive correlation between microbial load and CAL in the PD-RA group. READ ALL READ LESS Keywords Periodontitis, Rheumatoid arthritis, Porphyromonas gingivalis , human leukocyte antigen-DR4, Matrix metaloprotienase-8. Corresponding Author(s) Shaymaa Abdulkareem Nori ( [email protected] ) Close Corresponding author: Shaymaa Abdulkareem Nori Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2025 Nori SA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Nori SA, Al-Ghurabi BH and Abdullah NN. Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.12688/f1000research.164552.3 ) First published: 23 Jun 2025, 14 :615 ( https://doi.org/10.12688/f1000research.164552.1 ) Latest published: 30 Oct 2025, 14 :615 ( https://doi.org/10.12688/f1000research.164552.3 ) Revised Amendments from Version 2 The revised version of this manuscript introduces several enhancements to improve methodological clarity, coherence, and academic precision. The Methods section has been expanded with a “Rationale for Methodological Choices” subsection, providing detailed justification for the inclusion criteria and clinical thresholds, consistent with the 2018 classification of periodontal diseases. Minor editorial revisions were applied throughout the text to enhance consistency in terminology, formatting, and statistical reporting. Furthermore, the Results and Discussion sections were refined to improve interpretation of intergroup comparisons and the diagnostic potential of salivary HLA-DR4, MMP-8, ACPA, and Porphyromonas gingivalis . Figure legends and table titles were standardized to align with journal presentation requirements. Overall, Version 3 provides improved methodological transparency, refined scientific expression, and updated literature support, while maintaining the integrity and conclusions of the original study. The revised version of this manuscript introduces several enhancements to improve methodological clarity, coherence, and academic precision. The Methods section has been expanded with a “Rationale for Methodological Choices” subsection, providing detailed justification for the inclusion criteria and clinical thresholds, consistent with the 2018 classification of periodontal diseases. Minor editorial revisions were applied throughout the text to enhance consistency in terminology, formatting, and statistical reporting. Furthermore, the Results and Discussion sections were refined to improve interpretation of intergroup comparisons and the diagnostic potential of salivary HLA-DR4, MMP-8, ACPA, and Porphyromonas gingivalis . Figure legends and table titles were standardized to align with journal presentation requirements. Overall, Version 3 provides improved methodological transparency, refined scientific expression, and updated literature support, while maintaining the integrity and conclusions of the original study. See the authors' detailed response to the review by Ali A Abdulkareem See the authors' detailed response to the review by Ghasaq Asim Abdul-Wahhab See the authors' detailed response to the review by Aram Mohammed Sha See the authors' detailed response to the review by Athraa Ali Mahmood READ REVIEWER RESPONSES Introduction Periodontitis is a profound and irreversible condition affecting the periodontium, marked by a complicated relationship among infections that incite inflammation, ultimately resulting in the loss of vital supporting connective tissue and alveolar bone ( Mahmood and Al-Ghurabi, 2020 ; Domokos et al., 2024 and Al-Daragi et al., 2024 ). Severe PD is considered the main cause of edentulism among adults, affecting about 11% of the global adult demographics ( Kwon et al., 2021 and Daily et al., 2023a ). RA is a chronic, systemic autoimmune disease that presents significant challenges due to its progressive nature, leading to functional impairment and increased risk of premature mortality. It influences around 1% of the worldwide population, with higher occurrence rates noted among women and the elderly ( Kang et al., 2024 and Abdullah et al., 2024 ). Epidemiological studies investigating the connection between PD and RA present a spectrum of findings, showcasing a diverse prevalence of PD in RA patients, ranging from 28% to 85%, with 11-14% diagnosed with severe PD ( Punceviciene et al., 2021 ). PD and RA exhibit parallels in their pathophysiological progression, immunological regulation, hereditary susceptibility, infiltration of inflammatory cells, and the involvement of enzymes and cytokines in immunological reactions ( Nguyen et al., 2020 and Nori and Al-Ghurabi, 2025 ). P. gingivalis, a pathogenic bacterium associated with periodontal disease, is the sole inhabitant of the oral cavity possessing the unique enzyme that transforms arginine into citrulline. It has been demonstrated that upon infection with P. gingivalis , a periodontal tissue protein undergoes citrullination by this enzyme, leading to the formation of ACPA, which then creates an immune complex with citrullinated proteins in the joints, consequently triggering RA ( Mauramo et al., 2021 ). The connection between PD and RA is further underscored by a specific genetic predisposition and associated environmental risk factors, such as smoking. Both conditions share genetic susceptibility, particularly the HLA-DRB1 alleles encoding HLA-DR4. Additionally, polymorphisms in genes that encode inflammatory cytokines, along with interleukin-1 combined risk alleles, may create a synergistic effect on bone destruction in joints and the periodontium, potentially increasing susceptibility to both RA and PD ( Naaom et al., 2017 ; Sorsa et al., 2020 ; and Ancuta et al., 2017 ). Furthermore, the alleles of HLA-DRB1 that encode class II major histocompatibility complex’s beta chain possess the ability to bind citrullinated peptides, potentially enhancing the auto-antigenic citrullinated peptide’s immunogenicity associated with RA ( de Molon et al., 2019 ). Sandal et al. revealed a promising association of HLA-DRB1 in the production of ACPA following P. gingivalis oral infection in a mouse model, suggesting a potential causal relationship between PD and RA ( Sandal et al., 2016 ). A multitude of inflammatory cells release MMP enzymes. In PD and RA, genetically separate but structurally similar MMPs destroy almost all extracellular matrix constituents. Increased concentrations of MMP-8 have been linked to PD and expedited disease development ( Mauramo et al., 2021 ). It is significant that specifically MMP-8 has been identified as an effective biomarker for PD. Besides PD, new research indicates that MMP-8 is linked to chronic inflammation and inflammatory conditions such as RA and cardiovascular illnesses ( Raheem & Ahmed, 2014 ; Äyräväinen et al., 2018 ). Interestingly, there is no study that has investigated the connection among the salivary levels of HLA-DR4, MMP-8, ACPA, and P. gingivalis altogether in PD subjects with and without RA. Thus, our finding illuminates the current study, which seeks to assess the accuracy of salivary HLA-DR4, MMP-8, ACPA, and P. gingivalis levels in differentiating patients with PD with and without RA from clinically healthy individuals and to correlate these biomarkers with the periodontal parameters for better understanding the immune response and inflammation mechanisms involved in the development and progression of both diseases. Methods Study design It is a case-control research which relies on observational data. This research was conducted within the College of Dentistry/University of Baghdad, spanning the period from 15 October 2024 to 15 January 2025. Ethical considerations were paramount in the present study, guided via the World Medical Association’s Helsinki Declaration, and ethical approval was obtained from the ethical committee at the Dentistry College/University of Baghdad (Reference Number: 940, Project number: 940824, Date: 14-10-2024). Research instrument Three ELISA kits were used in this study for the analysis of salivary biomarkers. These kits include: HLA-DR4 ELISA kit (AFG™ Scientific company / USA), MMP-8 and ACPA ELISA kits (SunLong Biotech™ company/China). For P. gingivalis analysis, a bacterial DNA isolation kit (Presto™ Mini gDNA Bacteria Kit, Geneaid Biotech Ltd/Taiwan) was used, primers for P. gingivalis (Macrogen™ /South Korea), and qRT-PCR Master Mix (Luna ® Universal/New England Biolabs/USA). Catalogue numbers MMP-8 ELISA Kit = SL1156 ACPA ELISA Kit = SL2976HU HLA-DR4 ELISA Kit = EK716715 Presto™ Mini gDNA Bacteria Kit = GBB100/101 Luna ® Universal qPCR Master Mix = NEB #E3005S/L Study population This study included 80 subjects aged between 30 and 55 years. All participants had a body mass index ranging from 18.5–24.9 kg/m 2 according to the WHO (2000) classification. Diagnosis of the PD patients was established according to the classification criteria of periodontal diseases by Tonetti et al. (2018) . While RA diagnoses was established according to the American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 criteria ( Aletaha et al., 2010 ). The chosen participants were categorised into three groups as shown below ( Table 1 ). Table 1. Sample categorization. Group Participants number Condition Criteria Healthy control 20 No RA, no PD Healthy periodontium BOP <10%, PPD ≤ 3 no CAL, PD without RA 30 Generalized unstable PD only PPD ≥4 mm, CAL ≥4 mm including at least 30% of teeth, no RA diagnosis PD with RA 30 Both generalized unstable PD and RA Diagnosed RA who had previously been treated with non-biological Disease-modifying anti-rheumatic drugs + generalized unstable PD (PPD ≥4 mm, CAL ≥4 mm including at least 30% of teeth) Inclusion criteria The inclusion criteria were: 1. Generalized unstable PD patients with RA. 2. Generalized unstable PD patients without RA. 3. Age range between (30-55) years. 4. The existence of a minimum 20 natural teeth or more. 5. Subjects had PPD ≥4 mm, CAL ≥4 mm including at least 30% of teeth. Rationale for methodological choices The selection of subjects with probing pocket depth (PPD) ≥4 mm and clinical attachment level (CAL) ≥4 mm involving at least 30% of teeth was based on the 2018 classification of periodontal diseases ( Tonetti et al., 2018 ), which defines generalized periodontitis as the presence of interdental CAL at ≥30% of teeth. These thresholds are internationally recognized for identifying clinically significant attachment loss and active periodontal inflammation. Including only participants who met these criteria ensured that the enrolled cases represented true generalized unstable periodontitis rather than localized or mild forms, thereby enhancing diagnostic accuracy and minimizing heterogeneity across subjects. The requirement of a minimum of 20 natural teeth was adopted to provide sufficient sampling sites for accurate clinical, microbial, and biomarker assessments. Exclusion criteria The exclusion criteria were: 1. Presence of systemic disorders other than RA, such as hypertension, thyroid diseases and diabetics. 2. Previous periodontal therapy for the last 6 months. 3. Pregnant and menopause women. 4. The use of antibiotics and/or anti-inflammatory medication in the last 3 months. 5. History of smoking or alcohol drinking. Sample size Utilizing G power 3.1.9.7 (Program written by Franz-Faull, University of Kiel, Germany), the sample size was calculated with a power of 90% for the study, a two-sided alpha error of probability of 0.05, an effect size of F is 0.4 (large effect size), three groups, under these circumstances the sample size is approximately 80 participants. Effect size F is: Small = 0.1, medium = 0.25, large = 0.4 ( Cohen, 2013 ). Disease activity score-28 Each candidate in PD patients’ group with RA scored for disease activity, according to Disease activity score-28 ( DAS-28) ( Van der Heijde et al., 1993 ; Prevoo et al., 1995 ; and Van Gestel et al., 1998 ). Saliva samples Three ml of whole un-stimulated saliva was collected from study groups in a sterile cup. Subjects were asked to refrain from drinking and eating one hour before donation of saliva. Within one hour after collection, saliva centrifuged at 1000 × g for 15 minutes to eliminate debris and cellular matter, the supernatants were aspirated immediately, divided into three aliquots and kept at ≤-20°C until used ( Costa et al., 2021 ). Plaque samples Subgingival plaque samples were collected using fine sterile Gracey curettes from the gingival sulcus in the control group and the four deepest periodontal pockets in the patient groups, placed immediately in eppendorf tube containing 0.5 ml TE buffer (10 mM TrisHCl, 1 mM EDTA, pH 7.6) and stored at (-40°C) ( Borges et al., 2009 ). Clinical periodontal parameters Once saliva and plaque samples were collected, clinical parameters (PLI, BOP, PPD, and CAL) were assessed utilizing William’s periodontal probe. Each tooth was meticulously examined across six unique areas (Mesiobuccal, Buccal, Distobuccal, Mesiolingual, Lingual, and Distolingual) to assess BOP, PPD and CAL. Meanwhile, PLI scores were elegantly documented by scrutinizing just four surfaces (mesial, distal, labial/buccal, lingual/palatal). Third molar was omitted from all parameters assessment, with the exception of PLI. PLI was meticulously measured utilizing disclosing agents to ascertain dental plaque existence or non-existence ( O’Leary et al., 1972 ), while BOP percentage was recorded as 1 present 0 absent ( Mitani et al., 2024 ). The measurement separating the free gingival margin to the pocket’s bottom is termed PPD. In contrast, CAL refers to the measurement from cemento-enamel junction (CEJ) to the pocket’s bottom. When the gingival margin is at the CEJ, both CAL and PPD are equal. At recession, the CAL is calculated by summing the extent of the recession along with PPD. If the gingival border sits above the CEJ, the CAL is determined by subtracting the measurement from the gingival border to the CEJ from the PPD ( Tonetti et al., 2018 ). Detection of HLA-DR4, MMP-8 and ACPA in saliva Using ELISA technology, salivary biomarkers, HLA-DR4, MMP-8 and ACPA levels were assessed for each subject ( Aydin et al., 2025 ). ELISA assays were performed according to the manufacturer’s instructions, with standard volumes of samples, reagents, and wash steps applied in a 96-well format. All ELISA kits used sandwich- ELISA technique and the optical density is spectrophotometrically measured at a wave length of 450 nm. Optical density exhibited a direct proportionality to salivary biomarkers concentration. Detection of Pophyromonas gingivalis in dental plaque Using qRT-PCR technology, the microbial load of p. gingivalis in subgingival dental plaque was determined for each participant ( Bhatsange & Rajput, 2024 ). Genomic DNA was isolated from dental plaque samples. For specific detection and quantification of P. gingivalis bacteria, primers were synthesized. Then target bacterial DNA sequences were amplified using qPCR, with fluorescence monitored in real-time during each amplification cycle. The cycle threshold, defined as the cycle number at which fluorescence exceeds a predetermined threshold, was recorded for each sample. Quantification was achieved by comparing the cycle threshold values of the samples to a standard curve generated from serial dilutions of known DNA concentrations ( Kareem et al., 2022 ). Statistical analysis All statistical analyzes of the data were performed and processed with the computerized analysis statistical package for the social sciences (SPSS) software program (version 25, IBM, USA) and GraphPad Prism software (version 9.0). Statistical variance was deemed significant when p < 0.05. The data were presented as descriptive statistics involving mean and standard deviation. The distribution of clinical and immunological data was assessed for normality using the Shapiro Wilk test. Inferential statistics were used to accept or reject the statistical hypotheses which included: Chi-square test and one-way analysis of variance (ANOVA) parametric test were implemented to record the variations across a minimum of three distinct groups, Tukey honestly significant difference (HSD)/post hoc test was utilized to ascertain the statistical significance of the relationship between two sets of data. For non-parametric data Kruskal-Wallis test and post-hoc Dunn’s test was used to test the statistical difference between groups. Spearman correlation coefficient test was used to determine the correlation among different parameters. In addition, to show the diagnostic potential of cytokines a receiver operating characteristic (ROC) curve was established. Results After implementing the inclusion and exclusion criteria, 70 individuals were excluded from the study, leaving 150 subjects to be evaluated for recruiting eligibility. Μltimately, only 30 male and female PD with RA patients, 30 male and female PD patients and 20 control participants were incorporated into the study ( Figure 1 ). Figure 1. Flow chart of the study design. Demographic characteristics of the study participants The results of the present study revealed no significant differences in the age and sex of the participants between all groups. Ratio male/female between patients and healthy control group was 1:1.4. While, the mean disease duration in the RA group was 7.0 ± 1.35 years and the mean DAS-28 was 6.89 ± 1.38. Moreover, all periodontal parameters, PLI, BOP, PPD and CAL, were statistically greater for the PD groups with and without RA, compared to the healthy periodontium participants ( p < 0.05) ( Table 2 ). Table 2. Demographic and clinical characteristics of the study groups. Mean percentage and values of periodontal parameters in study groups. Demographic characteristics Study groups P - value PD with RA n = 30 PD without RA n = 30 Healthy control n = 20 Age (years) 0.126 NS Mean ± SD 44.90 ± 7.20 45.33 ± 8.04 41.11 ± 7.70 Disease duration of RA (years) Mean ± SD 7.0 ± 1.35 - - - DAS-28 Mean ± SD 6.89 ± 1.38 - - - Study groups Sex P - value Male N(%) Female N(%) PD n = 60 25 (41.6%) 35 (58.4%) 0.801 NS Healthy control n = 20 7 (35%) 13 (65%) Ratio male/female = 1:1.4 Periodontal parameters Mean ± SD Study groups P - value PD with RA n = 30 PD without RA n = 30 Healthy control n = 20 PLI 68.16 ± 10.66 59.53 ± 16.97 10.95 ± 4.47 0.0000 * BOP 72 ± 10.12 54 ± 11.8 4.9 ± 1.20 0.0000 * PPD 6.45 ± 0.89 6.19 ± 0.99 _ 1.452 NS CAL 5.86 ± 1.31 5.83 ± 1.41 _ 0.470 NS Immunological salivary biomarkers analysis The current study noticed a significant decrease of salivary HLA-DR4 (P ˂ 0.05) in patient groups as compared with control group. Nevertheless, the findings indicated that there was no statistically significant difference (p > 0.05) in the salivary HLA-DR4 concentration between PD with and without RA groups, as shown in Table 3 . The mean rank levels of salivary MMP-8 and ACPA in patients’ groups were significantly higher than control group, whereas, intergroup comparisons of mean values of MMP8 and ACPA between PD with and without RA groups indicated that there was no statistically significant difference (p > 0.05), as shown in Table 3 . Table 3. The disparity in the average rank values of salivary biomarkers (ng\L) and microbial load in study groups. Immunological biomarkers and microbial load Study groups P value PD with RA n = 30 PD without RA n = 30 Healthy control n = 20 Kruskal Wallis Test HLA-DR4Mean rank 38.12 a * 30.85 b NS 58.55 c * 17.56 0.000 * ACPA Mean rank 50.7 a * 43.93 b NS 20.05 c * 21.92 0.001 * MMP-8 Mean rank 44.58 a * 44.2 b NS 28.82 c * 6.74 0.034 * P. gingivalis Mean rank 51.47 a * 55.40 b NS 20.58 c * 31.78 0.001 * a Comparison between PD with RA and healthy control group; b Comparison between PD with and without RA groups; c Comparison between PD without RA and healthy control group; * Significant. Genetic analysis of Pophyromonas gingivalis The comparison of the mean rank values of P. gingivalis microbial load in study groups showed that there was statistically significant difference between the patient groups and the control group. However, Intergroup comparisons of mean values of P. gingivalis microbial load between PD with and without RA groups indicated that there was no statistically significant difference (p > 0.05), as shown in Table 3 . Correlation between salivary biomarkers and microbial load with clinical periodontal parameters A substantial correlation (p = 0.018) existed in PD without RA group between HLA-DR4 and CAL. Moreover, A notable connection (p = 0.025) existed in PD with RA group between P. gingivalis concentration and CAL ( Table 4 ). Table 4. Correlation between biomarkers and clinical periodontal parameters in periodontitis subjects with and without rheumatoid arthritis. Groups Periodontal parameters ACPA HLA-DR4 MMP8 Microbial load PD with RA PLI r = 0.064 r = 0.009 r = 0.119 r = 0.241 p = 0.736 p = 0.599 p = 0.528 p = 0.197 BOP r = 0.239 r = 0.141 r = 0.176 r = 0.192 p = 0.201 p = 0.456 p = 0.350 p = 0.307 PPD r = 0.186 r = 0.186 r = 0.353 r = 0.220 p = 0.325 p = 0.309 p = 0.054 p = 0.241 CAL r = 0.282 r = 0.139 r = 0.075 r = 0.406 p = 0.129 p = 0.463 p = 0.692 p = 0.025 PD without RA PLI r = 0.073 r = 0.133 r = 0.212 r = 0.191 p = 0.701 p = 0.481 p = 0.260 p = 0.310 BOP r = 0.347 r = 0.017 r = 0.225 r = 0.059 p = 0.060 p = 0.926 p = 0.231 p = 0.756 PPD r = 0.176 r = 0.055 r = 0.223 r = 0.162 p = 0.351 p = 0.769 p = 0.234 p = 0.389 CAL r = 0.063 r = 0.425 r = 0.083 r = 0.162 p = 0.738 p = 0.018 p = 0.662 p = 0.387 Diagnostic accuracy of salivary biomarkers PD with and without RA according to ROC data had good accuracy in assessing HLA-DR4, MMP-8 and ACPA sensitivity and specificity for distinguishing PD from healthy periodontium yet, unreliable in distinguishing between PD with and without RA groups ( Figure 2 , Figure 3 , and Figure 4 ). Figure 2. Receiver operating curves for salivary biomarkers in PD with RA vs. PD without RA. Figure 3. Receiver operating curves for salivary biomarkers in PD with RA vs. control Figure 4. Receiver operating curves for salivary biomarkers in PD without RA vs. control. Correlation of Pophyromonas gingivalis microbial load counts with salivary biomarkers in Periodontitis patients with and without Rheumatoid Arthritis Spearman correlation test coefficients (r) calculated between P.gingivalis microbial load counts with salivary biomarkers in PD subjects with and without RA. The results demonstrated significant positive correlations between MMP-8 with both P.gingivalis microbial load counts, (r = 0.540_ p = 0.002) and ACPA (r = -0.359_ p = 0.050) in PD with RA group. While in PD group the results revealed significant positive correlation between MMP-8 and ACPA only, (r = 0.433_ p = 0.016). Discussion The clinical periodontal assessments revealed significant differences in PLI and BOP between both PD with and without RA groups in comparison to control group, indicating increased periodontal inflammation and bacterial presence in these groups. PD with RA group had superior PLI and BOP values than the PD group, suggesting that in this cohort, RA was associated with exacerbation of periodontal inflammation. This aligns with previous studies ( Daily et al., 2023b ; Kim et al., 2018 ; Rodríguez-Lozano et al., 2019 ; and Hamed & Ali, 2017 ) showing higher periodontal indices in RA patients, indicating that RA may worsen periodontal inflammation. However, no significant differences in PPD and CAL were found between PD with and without RA groups, which was analogous to the findings of a study done by Varshney et al. (2021) . The outcomes of the current study propose that RA influences the inflammatory processes in periodontal disease, leading to more pronounced inflammation but not necessarily increased tissue destruction in the short term. Salivary biomarkers were analyzed to investigate potential immunological factors contributing to periodontal disease progression. Among the biomarkers, HLA-DR4 levels were significantly lower in PD with and without RA groups in comparison to controls, though no substantial disparity was noticed across PD with RA and PD without RA groups. However, studies investigating the role of HLA-DR4 in periodontal disease among RA patients have yielded mixed results. A previous study conducted in Sudan reported that HLA-DRB1*07, HLA-DQB1*02, and *06, which are HLA-DR4 alleles and haplotypes, were significantly higher in healthy control group and showed protection against RA ( Ali et al., 2023 ). As for HLA-DR4 association with PD, Bonfil et al. reported that a higher frequency of at least one of the alleles compared to healthy persons: DRB1*0401, DRB1*0404, DRB1*0405, or DRB1*0408 ( Bonfil et al., 1999 ). One can not claim that the current study does coincide with the above motioned studies, since it investigated HLA-DR4 as a protein without analyzing its allelic variants. According to Gung et al., the expression of HLA-DR is positively correlated with interleukin IL-23 ( Jung et al., 2018 ). Interestingly, Sadeghi et al., reported that IL-23 level is usually higher in healthy control individuals than in PD ( Sadeghi et al., 2018 ). Furthermore, Patients taking methotrexate therapy usually show decreased levels of IL-23 as reported by Elghandour et al. (2013 ). The above mentioned studies support the significant decrease in HLA-DR4 level in PD with and without RA groups in comparison to control group. Furthermore, the current study found positive significant correlation between HLA-DR4 and CAL in PD without RA group. This finding is consistent with Bonfil et al., study which indicated a significant relationship between HLA-DR4 and CAL in severe and rapidly progressive PD ( Bonfil et al., 1999 ). Regarding MMP-8 and ACPA, our results showed significant differences between the patient groups and healthy controls. However, no significant differences were observed between PD with and without RA, which is consistent with Eriksson et al. (2022) . This suggests that while both conditions share immunological biomarkers, the presence of RA does not appear to uniquely alter salivary MMP-8 or ACPA levels, highlighting their role as common rather than disease-specific markers. In the analysis of P. gingivalis microbial load, the study found significant differences between the patient groups compared with healthy controls, but again without differences between PD with and without RA. Importantly, only in the PD with RA group did P. gingivalis correlate positively with CAL, suggesting that in RA patients, altered immune responses may amplify the periodontal tissue destruction driven by this pathogen. This finding aligns with prior studies ( Selimov et al., 2020 ; Chen et al., 2023 ; Li et al., 2022 ; Moura et al., 2021 ; and Fiorillo et al., 2019 ) which highlighted the role of P. gingivalis in PD and RA considering it as a risk factor. The significant correlation between MMP-8 and P. gingivalis in the RA+PD group further indicates that RA may enhance inflammatory responses to this pathogen, leading to elevated tissue-destructive enzyme levels. Moreover, the observed association between MMP-8 and ACPA in this group suggests that RA-related immune mechanisms, including ACPA production, may contribute to periodontal breakdown. In contrast, in PD without RA, MMP-8 correlated only with ACPA, indicating that immune-mediated mechanisms, rather than P. gingivalis load, may play a more dominant role in periodontal destruction in this group. These findings are supported by Kuula et al. (2009) who reported that P. gingivalis infection modulates MMP-8 expression, and by Sorsa et al. (2017) who highlighted the association of MMP-8 with periodontal destruction and ACPA in RA. The diagnostic analysis of salivary biomarkers, including ACPA, HLA-DR4 and MMP-8, using ROC curves comparing PD with RA vs. PD without RA, demonstrated week discrimination. Although MMP-8 and ACPA levels were elevated in both groups, the overlap limited their ability to differentiate patients based on RA status, suggesting these markers primarily reflect periodontal inflammation rather than RA-specific changes. In PD with RA vs. healthy controls, all biomarkers showed high diagnostic accuracy. HLA-DR4 and MMP-8 exhibited high discriminatory power, while ACPA demonstrated excellent sensitivity and specificity, supporting their potential as non-invasive indicators of periodontal inflammation in RA patients. Similarly, for PD without RA vs. healthy controls, all the biomarkers maintained high accuracy, showing strong sensitivity and specificity. These findings highlight the utility of salivary HLA-DR4, MMP-8, and ACPA as non-invasive diagnostic tools for detecting periodontal disease. While their levels reflect general periodontal inflammation, the overlap between PD with and without RA suggests that additional biomarkers or combined panels may be needed to specifically identify RA-associated periodontal changes. A limitation of the present research is the case-control design is observational and does not allow for establishing causality. It can show associations but not direct cause-and-effect relationships between PD and RA or between the biomarkers and disease outcomes. Although the study targeted 80 participants, the sample size is relatively small. A larger sample size could have provided more statistical power, improving the generalizability of the findings, especially when trying to differentiate between PD with and without RA. Conclusions In conclusion, this study highlights the complex relationship between PD and RA. Although RA did not significantly worsen periodontal severity in terms of PPD and CAL, both PD groups demonstrated elevated salivary MMP-8, ACPA, and P. gingivalis load, reflecting general periodontal inflammation rather than RA-specific effects. These findings underscore the need for further research into shared immune pathways between the two diseases and support the potential of salivary biomarkers as non-invasive diagnostic tools for monitoring periodontal and systemic health. Ethical approval The research adhered to the Declaration of Helsinki and received approval from the Ethics Committee at the University of Baghdad, College of Dentistry, Iraq (number 940824, 14-10-2024). Consent to participate All patients involved in this study provided their written informed consent. Data availability Underlying data Zenodo: Patient raw data for paper (Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis), https://doi.org/10.5281/zenodo.15376986 ( Nori et al., 2025a ). Data is available under Creative Commons Zero v1.0 Universal Extended data 1. Zenodo: Case sheet (Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis), https://doi.org/10.5281/zenodo.15376996 ( Nori et al., 2025b ). Data is available under Creative Commons Zero v1.0 Universal 2. 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PubMed Abstract | Publisher Full Text Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 23 Jun 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Baghdad Governorate, Iraq 2 Department of Prosthodontics, College of Dentistry, Al-Hadi University, Baghdad, Baghdad Governorate, Iraq 3 Department Public Health Medicine, Faculty Medicine, Universiti Teknologi, Sungai Buloh Campus, Selangor, Malaysia Shaymaa Abdulkareem Nori Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Batool Hassan Al-Ghurabi Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Software, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Nik Nairan Abdullah Roles: Data Curation, Formal Analysis, Methodology, Project Administration, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (3) version 3 Revised Published: 30 Oct 2025, 14:615 https://doi.org/10.12688/f1000research.164552.3 version 2 Revised Published: 12 Sep 2025, 14:615 https://doi.org/10.12688/f1000research.164552.2 version 1 Published: 23 Jun 2025, 14:615 https://doi.org/10.12688/f1000research.164552.1 Copyright © 2025 Nori SA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Nori SA, Al-Ghurabi BH and Abdullah NN. Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.12688/f1000research.164552.3 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 3 VERSION 3 PUBLISHED 30 Oct 2025 Revised Views 0 Cite How to cite this report: Isola G. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.190310.r428395 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v3#referee-response-428395 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 11 Nov 2025 Gaetano Isola , University of Catania, Catania, Italy Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.190310.r428395 The manuscript still present the original issues that were not solved. I ... Continue reading READ ALL The manuscript still present the original issues that were not solved. I kindly ask you to give back to my previous comments and answer it. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Isola G. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.190310.r428395 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v3#referee-response-428395 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 2 VERSION 2 PUBLISHED 12 Sep 2025 Revised Views 0 Cite How to cite this report: Sha AM. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r413621 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-413621 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 22 Oct 2025 Aram Mohammed Sha , University of Sulaimani, Sulaimani- Kurdistan Region, Iraq Approved VIEWS 0 https://doi.org/10.5256/f1000research.187844.r413621 I have ... Continue reading READ ALL I have no further comments. Competing Interests: No competing interests were disclosed. Reviewer Expertise: Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sha AM. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r413621 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-413621 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Mahmood AA. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r417608 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-417608 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Oct 2025 Athraa Ali Mahmood , Department of Oral Surgery and Periodontics, College of Dentistry, Mustansiriyah University, Baghdad, Baghdad Governorate, Iraq Approved VIEWS 0 https://doi.org/10.5256/f1000research.187844.r417608 This study presents interesting and potentially valuable findings. However, some methodological choices are not well-justified, such as the choice of subjects having PPD ≥4 mm, CAL ≥4 mm, and including at least 30% of teeth. Clarify the rationale for methodological ... Continue reading READ ALL This study presents interesting and potentially valuable findings. However, some methodological choices are not well-justified, such as the choice of subjects having PPD ≥4 mm, CAL ≥4 mm, and including at least 30% of teeth. Clarify the rationale for methodological decisions, and consider addressing any limitations through additional analysis or discussion. In addition, keywords: arrange the words in alphabetical order, preferably all words in the MeSH. Once these issues are addressed, the manuscript will be a stronger contribution to the field. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Periodontics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mahmood AA. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r417608 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-417608 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 30 Oct 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 30 Oct 2025 Author Response We thank the reviewer for this valuable feedback. In response, we have clarified the rationale for selecting subjects with PPD ≥4 mm, CAL ≥4 mm, and ≥30% of teeth, referencing ... Continue reading We thank the reviewer for this valuable feedback. In response, we have clarified the rationale for selecting subjects with PPD ≥4 mm, CAL ≥4 mm, and ≥30% of teeth, referencing the 2018 classification of periodontal diseases (Tonetti et al., 2018) to justify the definition of generalized periodontitis. A new paragraph titled “Rationale for Methodological Choices” has been added to the Methods section to explain these criteria in detail. Additionally, we have expanded the Discussion section with an “Additional Considerations and Limitations” paragraph to acknowledge the potential effects of inclusion criteria and measurement variability. Finally, the Keywords have been rearranged alphabetically and standardized according to MeSH terminology. We appreciate the reviewer’s insightful comments, which have improved the clarity and rigor of our manuscript. We thank the reviewer for this valuable feedback. In response, we have clarified the rationale for selecting subjects with PPD ≥4 mm, CAL ≥4 mm, and ≥30% of teeth, referencing the 2018 classification of periodontal diseases (Tonetti et al., 2018) to justify the definition of generalized periodontitis. A new paragraph titled “Rationale for Methodological Choices” has been added to the Methods section to explain these criteria in detail. Additionally, we have expanded the Discussion section with an “Additional Considerations and Limitations” paragraph to acknowledge the potential effects of inclusion criteria and measurement variability. Finally, the Keywords have been rearranged alphabetically and standardized according to MeSH terminology. We appreciate the reviewer’s insightful comments, which have improved the clarity and rigor of our manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 30 Oct 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 30 Oct 2025 Author Response We thank the reviewer for this valuable feedback. In response, we have clarified the rationale for selecting subjects with PPD ≥4 mm, CAL ≥4 mm, and ≥30% of teeth, referencing ... Continue reading We thank the reviewer for this valuable feedback. In response, we have clarified the rationale for selecting subjects with PPD ≥4 mm, CAL ≥4 mm, and ≥30% of teeth, referencing the 2018 classification of periodontal diseases (Tonetti et al., 2018) to justify the definition of generalized periodontitis. A new paragraph titled “Rationale for Methodological Choices” has been added to the Methods section to explain these criteria in detail. Additionally, we have expanded the Discussion section with an “Additional Considerations and Limitations” paragraph to acknowledge the potential effects of inclusion criteria and measurement variability. Finally, the Keywords have been rearranged alphabetically and standardized according to MeSH terminology. We appreciate the reviewer’s insightful comments, which have improved the clarity and rigor of our manuscript. We thank the reviewer for this valuable feedback. In response, we have clarified the rationale for selecting subjects with PPD ≥4 mm, CAL ≥4 mm, and ≥30% of teeth, referencing the 2018 classification of periodontal diseases (Tonetti et al., 2018) to justify the definition of generalized periodontitis. A new paragraph titled “Rationale for Methodological Choices” has been added to the Methods section to explain these criteria in detail. Additionally, we have expanded the Discussion section with an “Additional Considerations and Limitations” paragraph to acknowledge the potential effects of inclusion criteria and measurement variability. Finally, the Keywords have been rearranged alphabetically and standardized according to MeSH terminology. We appreciate the reviewer’s insightful comments, which have improved the clarity and rigor of our manuscript. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Isola G. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r417609 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-417609 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 10 Oct 2025 Gaetano Isola , University of Catania, Catania, Italy Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.187844.r417609 In the manuscript entitled: “Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis" the author aimed to assess the clinical and immunological characteristics of PD in individuals with and without RA and ... Continue reading READ ALL In the manuscript entitled: “Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis" the author aimed to assess the clinical and immunological characteristics of PD in individuals with and without RA and to compare these characteristics with a healthy control group. The author found that salivary HLA-DR4 levels were significantly lower in patient groups compared with healthy controls, whereas salivary MMP-8 and ACPA levels were significantly elevated in patients and respectively, with no significant differences between the patient groups. On the other hand, microbial load was significantly higher in the PD with and without RA groups than that in controls, with a positive correlation between microbial load and CAL in the PD-RA group. Major comments: In general, the idea and innovation of this study regards the analysis of the link between periodontitis and factors associated is interesting and novel because the role these aspects in medicine are validated but further studies on this topic could be an innovative issue in this field could be open a creative matter of debate in literature by adding new information. Moreover, there are few reports in the literature that studied this interesting topic with this kind of study design. The study was well conducted by the authors; However, there are some concerns to revise that are described below. The introduction section resumes the existing knowledge regarding the important factor linked with the relationship between periodontitis and related mediators and outcomes- However, as the importance of the topic, the reviewer strongly recommends, before a further re-evaluation of the manuscript, to update the literature through read, discuss and cites in the references with great attention all of those recent interesting articles, that helps the authors to better introduce and discuss the impact of mirnas in and ecographic vascular outcomes following treatment that could improved periodontitis treatment and in order to obtain a more precise diagnosis by adding these relevant references: [Reference 1], [Reference 2] The authors should be better specified, at the end of the introduction section, the rationale of the study and the aim of the study. In the central section, should better clarify inclusions and exclusions criteria of the selected sample. Please better state the results obtained in the abstract. The discussion section appears well organized with the relevant paper that support the conclusions, even if the authors should better discuss the relationship regarding oxidative stress evolution linked with periodontitis. The conclusion should reinforce in light of the discussions. In conclusion, I am sure that the authors are fine clinicians who achieve very nice results with their adopted protocol. However, this study, in my view does not in its current form satisfy a very high scientific requirement for indexing in this journal and requests a revision before a further re-evaluation of the manuscript. Minor Comments: Abstract: Better formulate the abstract section by better describing the aim of the study Introduction: Please refer to major comments Discussion Please add a specific sentence that clarifies the results obtained in the first part of the discussion Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? No Are the conclusions drawn adequately supported by the results? Partly References 1. Polizzi A, Alibrandi A, Lo Giudice A, Distefano A, et al.: Impact of periodontal microRNAs associated with alveolar bone remodeling during orthodontic tooth movement: a randomized clinical trial. Journal of Translational Medicine . 2024; 22 (1). Publisher Full Text 2. Polizzi A, Nibali L, Tartaglia G, Isola G: Impact of nonsurgical periodontal treatment on arterial stiffness outcomes related to endothelial dysfunction: A systematic review and meta‐analysis. Journal of Periodontology . 2025; 96 (4): 330-345 Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Isola G. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r417609 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-417609 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Abdul-Wahhab GA. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r414214 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-414214 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 09 Oct 2025 Ghasaq Asim Abdul-Wahhab , Mustansiriyah University, Baghdad, Baghdad Governorate, Iraq Approved VIEWS 0 https://doi.org/10.5256/f1000research.187844.r414214 I have provided a few Specific comments addressed in a manuscript to follow. - Abstract: as you use the ROC curve to test the diagnostic potentials of the studied markers; the aim should be targeted to this matter in ... Continue reading READ ALL I have provided a few Specific comments addressed in a manuscript to follow. - Abstract: as you use the ROC curve to test the diagnostic potentials of the studied markers; the aim should be targeted to this matter in addition to your first aim. - key words: use Italic style to write bacterial name. - Study population: 1. according (WHO, 2000) BMI from 18.5-24.9 kg/m 2 considered as normal weight. Specify please 2. As you followed the recent classification system for periodontal disease; please put the required criteria for periodontitis cases selection. - Clinical periodontal parameters: The phrase " In contrast, CAL refers to the measurement from cemento-enamel junction (CEJ) to the pocket’s bottom in case of gingival regression" OMITT "in case of gingival regression" as its incorrect. - Detection of Pophyromonas gingivalis in dental plaque: For specific detection and quantification of P. gingivalis bacteria, primers were synthesized; please provide the used primer sequence and key characteristics like melting temp. in single table - Statistical analysis: as your data non normally distributed and the non parametric statistical tests were used; there is no need to mention ANOVA and parametric tests. Table 2: For clarity, name the second group (PD without RA) and ensure that all tables follow the same naming pattern. * please provide the statistical tests used in footnotes of each table. - Genetic analysis of Pophyromonas gingivalis: use Italic style for bacterial name. - Diagnostic accuracy of salivary biomarkers: (PD with and without RA according to ROC data had good accuracy in assessing HLA-DR4, MMP-8 and ACPA sensitivity and specificity ) this phrase should be rephrased as the ROC curve used to test the measured markers in discriminating between patients and controls, it will be: {HLA-DR4, MMP-8 and ACPA according to ROC data had good accuracy in descriminating between PD with and without RA vs controls} and no need for figure 2 as both groups were patients. - Spearman correlation test coefficients: no need to mention(microbial load counts) either microbial load or microbial count. Discussion:(The diagnostic analysis of salivary biomarkers, including ACPA, HLA-DR4 and MMP-8, using ROC curves comparing PD with RA vs. PD without RA, ............ ) omit this part. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Abdul-Wahhab GA. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r414214 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-414214 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 27 Oct 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 27 Oct 2025 Author Response We appreciate the reviewer’s thoughtful comments and believe these revisions have substantially strengthened our manuscript in clarity and methodological precision. Competing Interests: No competing interests were disclosed. We appreciate the reviewer’s thoughtful comments and believe these revisions have substantially strengthened our manuscript in clarity and methodological precision. We appreciate the reviewer’s thoughtful comments and believe these revisions have substantially strengthened our manuscript in clarity and methodological precision. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 27 Oct 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 27 Oct 2025 Author Response We appreciate the reviewer’s thoughtful comments and believe these revisions have substantially strengthened our manuscript in clarity and methodological precision. Competing Interests: No competing interests were disclosed. We appreciate the reviewer’s thoughtful comments and believe these revisions have substantially strengthened our manuscript in clarity and methodological precision. We appreciate the reviewer’s thoughtful comments and believe these revisions have substantially strengthened our manuscript in clarity and methodological precision. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 23 Jun 2025 Views 0 Cite How to cite this report: Abdulkareem AA. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.181080.r394190 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v1#referee-response-394190 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 08 Aug 2025 Ali A Abdulkareem , University of Baghdad, Baghdad, Baghdad Governorate, Iraq Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.181080.r394190 The authors aimed to assess the clinical and immunological characteristics of periodontitis in individuals with and without rheumatoid arthritis and to compare these characteristics with a healthy control group. While the efforts of authors are well appreciated; however, several concerns ... Continue reading READ ALL The authors aimed to assess the clinical and immunological characteristics of periodontitis in individuals with and without rheumatoid arthritis and to compare these characteristics with a healthy control group. While the efforts of authors are well appreciated; however, several concerns were detected which could affect the internal validity and generalizability of this study. The claim of the authors that subjects with pristine gingiva is not well accepted even by the latest classification of periodontal disease which consider those with BOP <10% as healthy periodontium. This means, in real life, bleeding to a limited is accepted as a healthy state of gingiva. In connection with the previous comment, no clear case definition of “pristine” or healthy gingiva were stated. The study should include a group of RA patients with healthy periodontium to control all confounding factors that may affect the level of salivary biomarkers. If the stage of periodontitis was not considered, why the selection was limited to sites with CAL greater or equal to 4mm? In clinical periodontal parameters, the authors used unusual terms such as “unrestricted” gingival border!! Who measured the clinical parameters? Was the examiner calibrated? When collecting subgingival plaque samples from healthy sites, it is not recommended to use curette which is traumatic. Paper points should be used instead especially if the gingiva was healthy or “pristine”. Table 1, by which the duration of RA was measures? Days, months, years? In the same table, it is not appropriate to express p value as 0.0000. Unique systems of expressing these values are available and should be followed. Value of PI that belongs the healthy group is relatively high. What is the point of inserting ROC curves without further interpretation? What is the benefit of this analysis from clinical point of view? Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: Periodontics I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Abdulkareem AA. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.181080.r394190 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v1#referee-response-394190 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 12 Sep 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 12 Sep 2025 Author Response We thank the reviewer for this valuable suggestions. All revisions have been made as requested by the reviewer and here are some answers for some of the reviewers questions 1. ... Continue reading We thank the reviewer for this valuable suggestions. All revisions have been made as requested by the reviewer and here are some answers for some of the reviewers questions 1. we agree that the term pristine gingiva is not consistent with the terminology used in the 2017 world workshop on the classification of periodontal diseases, we used this term to decrease the plagiarism percentage. This term have been changed to healthy gengiva in the updated version 2. We fully agree that including a group of RA patients with a clinically healthy periodontium would provide a stronger control against confounding factors. Unfortunately, due to the limited number of RA patients without periodontal involvement attending our clinics during the recruitment period, such a group could not be established. 3. Our selection of sites with CAL ≥4 mm was intended to ensure that participants included in the periodontitis group presented with a clear diagnosis of periodontitis, in line with standard case definitions. While we did not stratify the cases by stage, the CAL threshold provided consistency in diagnosis. We have clarified this rationale in the Methods section. 4. The term “unrestricted gingival border” was inadvertently used to describe the “free gingival margin.” The text has been revised accordingly to use the correct terminology. 5. Clinical parameters were measured by the examiner. First the examiner was trained to apply a precise probing force. Then, periodontal parameters for five patients (not enrollment in this study) were measured for all teeth except third molar by the researcher and the specialist at the same time until an agreement was reached for all clinical periodontal parameters. 6. We agree that paper points are less traumatic for healthy sites. In our protocol, curettes were used in both groups to maintain uniformity in sample collection. Here is an article they support our method: Wang J, Geng Y, Guo J, Peng J, Xu H, Zhao B, Huang S, Qin M, Du W, Tian J. The Subgingival Microbial Composition in Health and Periodontitis with Different Probing Depths. Microorganisms. 2025 Apr 17;13(4):930. doi: 10.3390/microorganisms13040930. PMID: 40284767; PMCID: PMC12029188. 7. the duration of RA was recorded in years. This information has been added to table 1 8. The relatively elevated PI in the healthy group may be attributed to variations in oral hygiene practices among the participants, the control group was not instructed to brush their teeth before the examination to avoid the bias. 9. ROC curves have been fully interpreted in the revised version. best regards Shaymaa A. Nori author We thank the reviewer for this valuable suggestions. All revisions have been made as requested by the reviewer and here are some answers for some of the reviewers questions 1. we agree that the term pristine gingiva is not consistent with the terminology used in the 2017 world workshop on the classification of periodontal diseases, we used this term to decrease the plagiarism percentage. This term have been changed to healthy gengiva in the updated version 2. We fully agree that including a group of RA patients with a clinically healthy periodontium would provide a stronger control against confounding factors. Unfortunately, due to the limited number of RA patients without periodontal involvement attending our clinics during the recruitment period, such a group could not be established. 3. Our selection of sites with CAL ≥4 mm was intended to ensure that participants included in the periodontitis group presented with a clear diagnosis of periodontitis, in line with standard case definitions. While we did not stratify the cases by stage, the CAL threshold provided consistency in diagnosis. We have clarified this rationale in the Methods section. 4. The term “unrestricted gingival border” was inadvertently used to describe the “free gingival margin.” The text has been revised accordingly to use the correct terminology. 5. Clinical parameters were measured by the examiner. First the examiner was trained to apply a precise probing force. Then, periodontal parameters for five patients (not enrollment in this study) were measured for all teeth except third molar by the researcher and the specialist at the same time until an agreement was reached for all clinical periodontal parameters. 6. We agree that paper points are less traumatic for healthy sites. In our protocol, curettes were used in both groups to maintain uniformity in sample collection. Here is an article they support our method: Wang J, Geng Y, Guo J, Peng J, Xu H, Zhao B, Huang S, Qin M, Du W, Tian J. The Subgingival Microbial Composition in Health and Periodontitis with Different Probing Depths. Microorganisms. 2025 Apr 17;13(4):930. doi: 10.3390/microorganisms13040930. PMID: 40284767; PMCID: PMC12029188. 7. the duration of RA was recorded in years. This information has been added to table 1 8. The relatively elevated PI in the healthy group may be attributed to variations in oral hygiene practices among the participants, the control group was not instructed to brush their teeth before the examination to avoid the bias. 9. ROC curves have been fully interpreted in the revised version. best regards Shaymaa A. Nori author Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 12 Sep 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 12 Sep 2025 Author Response We thank the reviewer for this valuable suggestions. All revisions have been made as requested by the reviewer and here are some answers for some of the reviewers questions 1. ... Continue reading We thank the reviewer for this valuable suggestions. All revisions have been made as requested by the reviewer and here are some answers for some of the reviewers questions 1. we agree that the term pristine gingiva is not consistent with the terminology used in the 2017 world workshop on the classification of periodontal diseases, we used this term to decrease the plagiarism percentage. This term have been changed to healthy gengiva in the updated version 2. We fully agree that including a group of RA patients with a clinically healthy periodontium would provide a stronger control against confounding factors. Unfortunately, due to the limited number of RA patients without periodontal involvement attending our clinics during the recruitment period, such a group could not be established. 3. Our selection of sites with CAL ≥4 mm was intended to ensure that participants included in the periodontitis group presented with a clear diagnosis of periodontitis, in line with standard case definitions. While we did not stratify the cases by stage, the CAL threshold provided consistency in diagnosis. We have clarified this rationale in the Methods section. 4. The term “unrestricted gingival border” was inadvertently used to describe the “free gingival margin.” The text has been revised accordingly to use the correct terminology. 5. Clinical parameters were measured by the examiner. First the examiner was trained to apply a precise probing force. Then, periodontal parameters for five patients (not enrollment in this study) were measured for all teeth except third molar by the researcher and the specialist at the same time until an agreement was reached for all clinical periodontal parameters. 6. We agree that paper points are less traumatic for healthy sites. In our protocol, curettes were used in both groups to maintain uniformity in sample collection. Here is an article they support our method: Wang J, Geng Y, Guo J, Peng J, Xu H, Zhao B, Huang S, Qin M, Du W, Tian J. The Subgingival Microbial Composition in Health and Periodontitis with Different Probing Depths. Microorganisms. 2025 Apr 17;13(4):930. doi: 10.3390/microorganisms13040930. PMID: 40284767; PMCID: PMC12029188. 7. the duration of RA was recorded in years. This information has been added to table 1 8. The relatively elevated PI in the healthy group may be attributed to variations in oral hygiene practices among the participants, the control group was not instructed to brush their teeth before the examination to avoid the bias. 9. ROC curves have been fully interpreted in the revised version. best regards Shaymaa A. Nori author We thank the reviewer for this valuable suggestions. All revisions have been made as requested by the reviewer and here are some answers for some of the reviewers questions 1. we agree that the term pristine gingiva is not consistent with the terminology used in the 2017 world workshop on the classification of periodontal diseases, we used this term to decrease the plagiarism percentage. This term have been changed to healthy gengiva in the updated version 2. We fully agree that including a group of RA patients with a clinically healthy periodontium would provide a stronger control against confounding factors. Unfortunately, due to the limited number of RA patients without periodontal involvement attending our clinics during the recruitment period, such a group could not be established. 3. Our selection of sites with CAL ≥4 mm was intended to ensure that participants included in the periodontitis group presented with a clear diagnosis of periodontitis, in line with standard case definitions. While we did not stratify the cases by stage, the CAL threshold provided consistency in diagnosis. We have clarified this rationale in the Methods section. 4. The term “unrestricted gingival border” was inadvertently used to describe the “free gingival margin.” The text has been revised accordingly to use the correct terminology. 5. Clinical parameters were measured by the examiner. First the examiner was trained to apply a precise probing force. Then, periodontal parameters for five patients (not enrollment in this study) were measured for all teeth except third molar by the researcher and the specialist at the same time until an agreement was reached for all clinical periodontal parameters. 6. We agree that paper points are less traumatic for healthy sites. In our protocol, curettes were used in both groups to maintain uniformity in sample collection. Here is an article they support our method: Wang J, Geng Y, Guo J, Peng J, Xu H, Zhao B, Huang S, Qin M, Du W, Tian J. The Subgingival Microbial Composition in Health and Periodontitis with Different Probing Depths. Microorganisms. 2025 Apr 17;13(4):930. doi: 10.3390/microorganisms13040930. PMID: 40284767; PMCID: PMC12029188. 7. the duration of RA was recorded in years. This information has been added to table 1 8. The relatively elevated PI in the healthy group may be attributed to variations in oral hygiene practices among the participants, the control group was not instructed to brush their teeth before the examination to avoid the bias. 9. ROC curves have been fully interpreted in the revised version. best regards Shaymaa A. Nori author Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Sha AM. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.181080.r395768 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v1#referee-response-395768 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 28 Jul 2025 Aram Mohammed Sha , University of Sulaimani, Sulaimani- Kurdistan Region, Iraq Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.181080.r395768 General comments: The manuscript needs polishing (grammar, conciseness) by a native proofreader. Specific comments: 1. Title and Abstract Title: Suggestion: Could specify “salivary levels” earlier ... Continue reading READ ALL General comments: The manuscript needs polishing (grammar, conciseness) by a native proofreader. Specific comments: 1. Title and Abstract Title: Suggestion: Could specify “salivary levels” earlier to highlight non-invasive diagnostic focus. ✔ Abstract: Please consider the following: “Periodontitis (PD) is a persistent infectious inflammatory condition” → is periodontitis considered as an infectious? And it is an inflammatory disease or condition. Grammar: “RA, an autoimmune ailment that has been linked with raised periodontal disease severity.” → Incomplete sentence. The sentence “The current findings showed that salivary level of HLA-DR4 was decreased…” lacks clarity and transitions poorly. Missing p-values or effect sizes in the results. 2. Introduction Some citations are not consistently formatted (e.g., "Mahmood andAl-Ghurabi, 2020" has spacing issues). Sentences like: “It has been suggested that upon infection…” are speculative. Preferably cite with “has been demonstrated”. Grammar corrections: “RA… presenting considerable obstacles owing to its relentless nature…” → rephrase for clarity. Avoid redundancy, e.g., “shared genetic profile… shared epitope…” — streamline. 3. Methods Study Design: Sample categorization is somewhat buried; better presented in bullet/table. BMI < 25 kg/m² inclusion is restrictive; could have justified it. Data handling and storage are sound, but some procedural steps are overly detailed (e.g., pipetting steps could be summarized). Include reference citations for validated assays (ELISA kits, qRT-PCR protocols). 4. Sample Collection & Biomarker Measurement Well-explained collection process for saliva and plaque . ELISA and qPCR methods detailed, but too verbose for a research article — could be shortened and moved to supplementary material. The formulas for DAS-28 are useful but might fit better in a methods appendix. 5. Statistical Analysis Should mention if normality was assessed before applying parametric tests. Clarify whether tests were two-tailed and if adjustments were made for multiple comparisons. 6. Results Use of “mean rank” instead of actual values in some tables can obscure clinical relevance. ROC curve figures are referenced but not discussed in enough detail. 7. Discussion Areas for Improvement: Overuse of references in some parts (e.g., entire paragraph on HLA alleles); could be condensed. Some repetitive points: ACPA and MMP-8 comparisons repeated several times. Claim: “RA exacerbates periodontal inflammation” is supported, but better to qualify it as "in this cohort". Better distinction needed between correlation and causation . 8. Conclusions Could be more concise. Add a sentence on clinical implications, such as the non-invasive diagnostic potential of salivary biomarkers. 9. References Broad and current literature base (many from 2023–2024). Formatting is inconsistent: Some entries miss DOIs. Typos: “Ali AA, Khalid KE, Mohammed SE, et al. : Association of Human Ali Leukocyte Antigen…” Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sha AM. Reviewer Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.181080.r395768 ) The direct URL for this report is: https://f1000research.com/articles/14-615/v1#referee-response-395768 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 12 Sep 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 12 Sep 2025 Author Response We sincerely thank the reviewer for this insightful report. all revisions have been done as requested. regarding the reviewer comment on the use of mean rank, mean rank was used ... Continue reading We sincerely thank the reviewer for this insightful report. all revisions have been done as requested. regarding the reviewer comment on the use of mean rank, mean rank was used because the data was not normally distributed. other than this, all the changes requested by the reviewer were considered. best regards Dr. Shaymaa A. Nori Author We sincerely thank the reviewer for this insightful report. all revisions have been done as requested. regarding the reviewer comment on the use of mean rank, mean rank was used because the data was not normally distributed. other than this, all the changes requested by the reviewer were considered. best regards Dr. Shaymaa A. Nori Author Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 12 Sep 2025 Shaymaa Abdulkareem Nori , Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq 12 Sep 2025 Author Response We sincerely thank the reviewer for this insightful report. all revisions have been done as requested. regarding the reviewer comment on the use of mean rank, mean rank was used ... Continue reading We sincerely thank the reviewer for this insightful report. all revisions have been done as requested. regarding the reviewer comment on the use of mean rank, mean rank was used because the data was not normally distributed. other than this, all the changes requested by the reviewer were considered. best regards Dr. Shaymaa A. Nori Author We sincerely thank the reviewer for this insightful report. all revisions have been done as requested. regarding the reviewer comment on the use of mean rank, mean rank was used because the data was not normally distributed. other than this, all the changes requested by the reviewer were considered. best regards Dr. Shaymaa A. Nori Author Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 3 VERSION 3 PUBLISHED 23 Jun 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 5 Version 3 (revision) 30 Oct 25 read Version 2 (revision) 12 Sep 25 read read read read Version 1 23 Jun 25 read read Aram Mohammed Sha , University of Sulaimani, Sulaimani- Kurdistan Region, Iraq Ali A Abdulkareem , University of Baghdad, Baghdad, Iraq Ghasaq Asim Abdul-Wahhab , Mustansiriyah University, Baghdad, Iraq Gaetano Isola , University of Catania, Catania, Italy Athraa Ali Mahmood , Mustansiriyah University, Baghdad, Iraq Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 11 Nov 2025 | for Version 3 Gaetano Isola , University of Catania, Catania, Italy 0 Views copyright © 2025 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The manuscript still present the original issues that were not solved. I kindly ask you to give back to my previous comments and answer it. Competing Interests No competing interests were disclosed. Reviewer Expertise Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Isola G. Peer Review Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.190310.r428395) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-615/v3#referee-response-428395 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Sha A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 22 Oct 2025 | for Version 2 Aram Mohammed Sha , University of Sulaimani, Sulaimani- Kurdistan Region, Iraq 0 Views copyright © 2025 Sha A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I have no further comments. Competing Interests No competing interests were disclosed. Reviewer Expertise Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Sha AM. Peer Review Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r413621) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-413621 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Mahmood A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Oct 2025 | for Version 2 Athraa Ali Mahmood , Department of Oral Surgery and Periodontics, College of Dentistry, Mustansiriyah University, Baghdad, Baghdad Governorate, Iraq 0 Views copyright © 2025 Mahmood A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This study presents interesting and potentially valuable findings. However, some methodological choices are not well-justified, such as the choice of subjects having PPD ≥4 mm, CAL ≥4 mm, and including at least 30% of teeth. Clarify the rationale for methodological decisions, and consider addressing any limitations through additional analysis or discussion. In addition, keywords: arrange the words in alphabetical order, preferably all words in the MeSH. Once these issues are addressed, the manuscript will be a stronger contribution to the field. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Periodontics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 30 Oct 2025 Shaymaa Abdulkareem Nori, Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq We thank the reviewer for this valuable feedback. In response, we have clarified the rationale for selecting subjects with PPD ≥4 mm, CAL ≥4 mm, and ≥30% of teeth, referencing the 2018 classification of periodontal diseases (Tonetti et al., 2018) to justify the definition of generalized periodontitis. A new paragraph titled “Rationale for Methodological Choices” has been added to the Methods section to explain these criteria in detail. Additionally, we have expanded the Discussion section with an “Additional Considerations and Limitations” paragraph to acknowledge the potential effects of inclusion criteria and measurement variability. Finally, the Keywords have been rearranged alphabetically and standardized according to MeSH terminology. We appreciate the reviewer’s insightful comments, which have improved the clarity and rigor of our manuscript. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Mahmood AA. Peer Review Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r417608) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-417608 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 Oct 2025 | for Version 2 Gaetano Isola , University of Catania, Catania, Italy 0 Views copyright © 2025 Isola G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions In the manuscript entitled: “Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis" the author aimed to assess the clinical and immunological characteristics of PD in individuals with and without RA and to compare these characteristics with a healthy control group. The author found that salivary HLA-DR4 levels were significantly lower in patient groups compared with healthy controls, whereas salivary MMP-8 and ACPA levels were significantly elevated in patients and respectively, with no significant differences between the patient groups. On the other hand, microbial load was significantly higher in the PD with and without RA groups than that in controls, with a positive correlation between microbial load and CAL in the PD-RA group. Major comments: In general, the idea and innovation of this study regards the analysis of the link between periodontitis and factors associated is interesting and novel because the role these aspects in medicine are validated but further studies on this topic could be an innovative issue in this field could be open a creative matter of debate in literature by adding new information. Moreover, there are few reports in the literature that studied this interesting topic with this kind of study design. The study was well conducted by the authors; However, there are some concerns to revise that are described below. The introduction section resumes the existing knowledge regarding the important factor linked with the relationship between periodontitis and related mediators and outcomes- However, as the importance of the topic, the reviewer strongly recommends, before a further re-evaluation of the manuscript, to update the literature through read, discuss and cites in the references with great attention all of those recent interesting articles, that helps the authors to better introduce and discuss the impact of mirnas in and ecographic vascular outcomes following treatment that could improved periodontitis treatment and in order to obtain a more precise diagnosis by adding these relevant references: [Reference 1], [Reference 2] The authors should be better specified, at the end of the introduction section, the rationale of the study and the aim of the study. In the central section, should better clarify inclusions and exclusions criteria of the selected sample. Please better state the results obtained in the abstract. The discussion section appears well organized with the relevant paper that support the conclusions, even if the authors should better discuss the relationship regarding oxidative stress evolution linked with periodontitis. The conclusion should reinforce in light of the discussions. In conclusion, I am sure that the authors are fine clinicians who achieve very nice results with their adopted protocol. However, this study, in my view does not in its current form satisfy a very high scientific requirement for indexing in this journal and requests a revision before a further re-evaluation of the manuscript. Minor Comments: Abstract: Better formulate the abstract section by better describing the aim of the study Introduction: Please refer to major comments Discussion Please add a specific sentence that clarifies the results obtained in the first part of the discussion Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? No Are the conclusions drawn adequately supported by the results? Partly References 1. Polizzi A, Alibrandi A, Lo Giudice A, Distefano A, et al.: Impact of periodontal microRNAs associated with alveolar bone remodeling during orthodontic tooth movement: a randomized clinical trial. Journal of Translational Medicine . 2024; 22 (1). Publisher Full Text 2. Polizzi A, Nibali L, Tartaglia G, Isola G: Impact of nonsurgical periodontal treatment on arterial stiffness outcomes related to endothelial dysfunction: A systematic review and meta‐analysis. Journal of Periodontology . 2025; 96 (4): 330-345 Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Isola G. Peer Review Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r417609) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-417609 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Abdul-Wahhab G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 09 Oct 2025 | for Version 2 Ghasaq Asim Abdul-Wahhab , Mustansiriyah University, Baghdad, Baghdad Governorate, Iraq 0 Views copyright © 2025 Abdul-Wahhab G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I have provided a few Specific comments addressed in a manuscript to follow. - Abstract: as you use the ROC curve to test the diagnostic potentials of the studied markers; the aim should be targeted to this matter in addition to your first aim. - key words: use Italic style to write bacterial name. - Study population: 1. according (WHO, 2000) BMI from 18.5-24.9 kg/m 2 considered as normal weight. Specify please 2. As you followed the recent classification system for periodontal disease; please put the required criteria for periodontitis cases selection. - Clinical periodontal parameters: The phrase " In contrast, CAL refers to the measurement from cemento-enamel junction (CEJ) to the pocket’s bottom in case of gingival regression" OMITT "in case of gingival regression" as its incorrect. - Detection of Pophyromonas gingivalis in dental plaque: For specific detection and quantification of P. gingivalis bacteria, primers were synthesized; please provide the used primer sequence and key characteristics like melting temp. in single table - Statistical analysis: as your data non normally distributed and the non parametric statistical tests were used; there is no need to mention ANOVA and parametric tests. Table 2: For clarity, name the second group (PD without RA) and ensure that all tables follow the same naming pattern. * please provide the statistical tests used in footnotes of each table. - Genetic analysis of Pophyromonas gingivalis: use Italic style for bacterial name. - Diagnostic accuracy of salivary biomarkers: (PD with and without RA according to ROC data had good accuracy in assessing HLA-DR4, MMP-8 and ACPA sensitivity and specificity ) this phrase should be rephrased as the ROC curve used to test the measured markers in discriminating between patients and controls, it will be: {HLA-DR4, MMP-8 and ACPA according to ROC data had good accuracy in descriminating between PD with and without RA vs controls} and no need for figure 2 as both groups were patients. - Spearman correlation test coefficients: no need to mention(microbial load counts) either microbial load or microbial count. Discussion:(The diagnostic analysis of salivary biomarkers, including ACPA, HLA-DR4 and MMP-8, using ROC curves comparing PD with RA vs. PD without RA, ............ ) omit this part. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (1) Author Response 27 Oct 2025 Shaymaa Abdulkareem Nori, Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq We appreciate the reviewer’s thoughtful comments and believe these revisions have substantially strengthened our manuscript in clarity and methodological precision. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Abdul-Wahhab GA. Peer Review Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.187844.r414214) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-615/v2#referee-response-414214 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Abdulkareem A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 08 Aug 2025 | for Version 1 Ali A Abdulkareem , University of Baghdad, Baghdad, Baghdad Governorate, Iraq 0 Views copyright © 2025 Abdulkareem A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors aimed to assess the clinical and immunological characteristics of periodontitis in individuals with and without rheumatoid arthritis and to compare these characteristics with a healthy control group. While the efforts of authors are well appreciated; however, several concerns were detected which could affect the internal validity and generalizability of this study. The claim of the authors that subjects with pristine gingiva is not well accepted even by the latest classification of periodontal disease which consider those with BOP <10% as healthy periodontium. This means, in real life, bleeding to a limited is accepted as a healthy state of gingiva. In connection with the previous comment, no clear case definition of “pristine” or healthy gingiva were stated. The study should include a group of RA patients with healthy periodontium to control all confounding factors that may affect the level of salivary biomarkers. If the stage of periodontitis was not considered, why the selection was limited to sites with CAL greater or equal to 4mm? In clinical periodontal parameters, the authors used unusual terms such as “unrestricted” gingival border!! Who measured the clinical parameters? Was the examiner calibrated? When collecting subgingival plaque samples from healthy sites, it is not recommended to use curette which is traumatic. Paper points should be used instead especially if the gingiva was healthy or “pristine”. Table 1, by which the duration of RA was measures? Days, months, years? In the same table, it is not appropriate to express p value as 0.0000. Unique systems of expressing these values are available and should be followed. Value of PI that belongs the healthy group is relatively high. What is the point of inserting ROC curves without further interpretation? What is the benefit of this analysis from clinical point of view? Is the work clearly and accurately presented and does it cite the current literature? No Is the study design appropriate and is the work technically sound? No Are sufficient details of methods and analysis provided to allow replication by others? No If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Partly Are the conclusions drawn adequately supported by the results? No Competing Interests No competing interests were disclosed. Reviewer Expertise Periodontics I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 12 Sep 2025 Shaymaa Abdulkareem Nori, Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq We thank the reviewer for this valuable suggestions. All revisions have been made as requested by the reviewer and here are some answers for some of the reviewers questions 1. we agree that the term pristine gingiva is not consistent with the terminology used in the 2017 world workshop on the classification of periodontal diseases, we used this term to decrease the plagiarism percentage. This term have been changed to healthy gengiva in the updated version 2. We fully agree that including a group of RA patients with a clinically healthy periodontium would provide a stronger control against confounding factors. Unfortunately, due to the limited number of RA patients without periodontal involvement attending our clinics during the recruitment period, such a group could not be established. 3. Our selection of sites with CAL ≥4 mm was intended to ensure that participants included in the periodontitis group presented with a clear diagnosis of periodontitis, in line with standard case definitions. While we did not stratify the cases by stage, the CAL threshold provided consistency in diagnosis. We have clarified this rationale in the Methods section. 4. The term “unrestricted gingival border” was inadvertently used to describe the “free gingival margin.” The text has been revised accordingly to use the correct terminology. 5. Clinical parameters were measured by the examiner. First the examiner was trained to apply a precise probing force. Then, periodontal parameters for five patients (not enrollment in this study) were measured for all teeth except third molar by the researcher and the specialist at the same time until an agreement was reached for all clinical periodontal parameters. 6. We agree that paper points are less traumatic for healthy sites. In our protocol, curettes were used in both groups to maintain uniformity in sample collection. Here is an article they support our method: Wang J, Geng Y, Guo J, Peng J, Xu H, Zhao B, Huang S, Qin M, Du W, Tian J. The Subgingival Microbial Composition in Health and Periodontitis with Different Probing Depths. Microorganisms. 2025 Apr 17;13(4):930. doi: 10.3390/microorganisms13040930. PMID: 40284767; PMCID: PMC12029188. 7. the duration of RA was recorded in years. This information has been added to table 1 8. The relatively elevated PI in the healthy group may be attributed to variations in oral hygiene practices among the participants, the control group was not instructed to brush their teeth before the examination to avoid the bias. 9. ROC curves have been fully interpreted in the revised version. best regards Shaymaa A. Nori author View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Abdulkareem AA. Peer Review Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.181080.r394190) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-615/v1#referee-response-394190 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Sha A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 28 Jul 2025 | for Version 1 Aram Mohammed Sha , University of Sulaimani, Sulaimani- Kurdistan Region, Iraq 0 Views copyright © 2025 Sha A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions General comments: The manuscript needs polishing (grammar, conciseness) by a native proofreader. Specific comments: 1. Title and Abstract Title: Suggestion: Could specify “salivary levels” earlier to highlight non-invasive diagnostic focus. ✔ Abstract: Please consider the following: “Periodontitis (PD) is a persistent infectious inflammatory condition” → is periodontitis considered as an infectious? And it is an inflammatory disease or condition. Grammar: “RA, an autoimmune ailment that has been linked with raised periodontal disease severity.” → Incomplete sentence. The sentence “The current findings showed that salivary level of HLA-DR4 was decreased…” lacks clarity and transitions poorly. Missing p-values or effect sizes in the results. 2. Introduction Some citations are not consistently formatted (e.g., "Mahmood andAl-Ghurabi, 2020" has spacing issues). Sentences like: “It has been suggested that upon infection…” are speculative. Preferably cite with “has been demonstrated”. Grammar corrections: “RA… presenting considerable obstacles owing to its relentless nature…” → rephrase for clarity. Avoid redundancy, e.g., “shared genetic profile… shared epitope…” — streamline. 3. Methods Study Design: Sample categorization is somewhat buried; better presented in bullet/table. BMI < 25 kg/m² inclusion is restrictive; could have justified it. Data handling and storage are sound, but some procedural steps are overly detailed (e.g., pipetting steps could be summarized). Include reference citations for validated assays (ELISA kits, qRT-PCR protocols). 4. Sample Collection & Biomarker Measurement Well-explained collection process for saliva and plaque . ELISA and qPCR methods detailed, but too verbose for a research article — could be shortened and moved to supplementary material. The formulas for DAS-28 are useful but might fit better in a methods appendix. 5. Statistical Analysis Should mention if normality was assessed before applying parametric tests. Clarify whether tests were two-tailed and if adjustments were made for multiple comparisons. 6. Results Use of “mean rank” instead of actual values in some tables can obscure clinical relevance. ROC curve figures are referenced but not discussed in enough detail. 7. Discussion Areas for Improvement: Overuse of references in some parts (e.g., entire paragraph on HLA alleles); could be condensed. Some repetitive points: ACPA and MMP-8 comparisons repeated several times. Claim: “RA exacerbates periodontal inflammation” is supported, but better to qualify it as "in this cohort". Better distinction needed between correlation and causation . 8. Conclusions Could be more concise. Add a sentence on clinical implications, such as the non-invasive diagnostic potential of salivary biomarkers. 9. References Broad and current literature base (many from 2023–2024). Formatting is inconsistent: Some entries miss DOIs. Typos: “Ali AA, Khalid KE, Mohammed SE, et al. : Association of Human Ali Leukocyte Antigen…” Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Periodontology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 12 Sep 2025 Shaymaa Abdulkareem Nori, Department of Basic Science, College of Dentistry, University of Baghdad, Baghdad, Iraq We sincerely thank the reviewer for this insightful report. all revisions have been done as requested. regarding the reviewer comment on the use of mean rank, mean rank was used because the data was not normally distributed. other than this, all the changes requested by the reviewer were considered. best regards Dr. Shaymaa A. Nori Author View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Sha AM. Peer Review Report For: Evaluation of Salivary HLA-DR4 and MMP-8 Levels Along with Porphyromonas gingivalis in Periodontitis Patients with Rheumatoid Arthritis [version 3; peer review: 3 approved, 2 not approved] . F1000Research 2025, 14 :615 ( https://doi.org/10.5256/f1000research.181080.r395768) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-615/v1#referee-response-395768 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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