Periodontal Health and Chitinase 3-Like-1 Levels in Autoimmune Rheumatic Diseases and Osteoarthritis 

Periodontal Health and Chitinase 3-Like-1 Levels in Autoimmune Rheumatic Diseases and Osteoarthritis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Periodontal Health and Chitinase 3-Like-1 Levels in Autoimmune Rheumatic Diseases and Osteoarthritis Adam Lukac, Eva Buchalova, Jana Sistkova, Lucie Buresova, Petr Nemec, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8305752/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background Autoimmune rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), often co-exist with periodontitis (PD). Both diseases share inflammatory pathways and common risk factors, suggesting a potential interplay. This study evaluates the association between periodontal health and Chitinase 3-Like-1 (CHI3L1), a serological marker of cartilage damage, in patients with or without AIRD. Methods In a cross-sectional design, 36 participants (AIRD patients and controls) underwent rheumatological and periodontal assessments. Clinical data included inflammatory markers, CHI3L1 levels, and detailed periodontal health metrics. Statistical analyses were performed to examine differences between groups and correlations between periodontal indices and CHI3L1 concentrations, adjusting for age and sex. Results While no significant differences in CHI3L1 levels were found between AIRD and control groups, male participants and individuals with higher Plaque Index (PI) scores exhibited significantly elevated CHI3L1 concentrations. Linear regression indicated PI as a significant predictor of CHI3L1 levels, with a 62% increase per PI unit. The AIRD group showed higher inflammatory marker levels overall. Conclusions CHI3L1 levels correlated with the severity of periodontal disease, with higher concentrations observed in individuals with poorer oral health. These findings indicate that CHI3L1 is associated with periodontitis independently of the presence of AIRD in patients presenting with joint pain. Further longitudinal studies are needed to clarify causal relationships and to determine whether improving periodontal health can reduce systemic inflammation in patients with AIRD. Rheumatoid arthritis Periodontitis Oral microbiota Citrullination Systemic inflammation Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Early presentations of autoimmune inflammatory rheumatic diseases (AIRD) often manifest as joint inflammation without an immediately identifiable etiology. At this stage, the differential diagnosis spans a broad spectrum of disorders, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (AxSpA), osteoarthritis with inflammatory features (OA), and systemic connective tissue diseases such as systemic lupus erythematosus (SLE). ( 1 ) Understanding this diagnostic uncertainty is critical for guiding early management and preventing long-term disease progression. Among these diseases, the connection between periodontitis (PD) and rheumatoid arthritis is the most evident. Both diseases exhibit certain similar features in their pathogenic processes and a similar ability to cause bone destruction at sites of inflammation. Additionally, both diseases share some common risk factors, including smoking, obesity, socioeconomic status, and genetic factors (HLA-DRB1). Periodontitis is an inflammatory disease characterized by the pathological loss of periodontal ligaments and alveolar bone. It is a multifactorial disease involving a dynamic interaction between pathogenic microorganisms and a destructive immune response. ( 2 ) PD is a prevalent disease affecting up to 47% of the adult population and leads to gum bleeding with the translocation of oral bacteria into the bloodstream. In its advanced stages, PD leads to tooth loss and a reduction in quality of life. ( 3 , 4 ) PD is more common in patients with rheumatoid arthritis (RA), especially in RA with anti-citrullinated protein antibodies (ACPAs). ( 5 ) Periodontal therapy is locally effective in patients with rheumatoid arthritis and, in those with severe periodontitis, is associated with reductions in RA disease activity and ACPA levels, suggesting that PD may trigger systemic inflammatory pathways relevant to ongoing joint inflammation. ( 6 ) Periodontitis associates with rheumatoid arthritis from early disease stages. RA treatments outside some biological DMARDs are ineffective in treatment of periodontitis which highlight the unmet need to identify RA at risk of periodontitis early and to prioritise them for specialist periodontal therapies. ( 7 , 10 ) The connection between periodontitis and other common diseases causing autoimmune arthritis (e.g. SLE, PsA, AxSpa) remains largely elusive with some suggestions of higher incidence of periodontitis in patients with SLE, and direct correlation with disease activity. ( 8 ) Chitinase 3-Like-1 (CHI3L1) features in pathogenies of both RA and periodontitis. This cartilage-derived protein is increasingly recognized in joint damage. Elevated CHI3L1 levels have also been observed in patients with hip OA, further underscoring its relevance as an indicator of cartilage damage. ( 9 ) The aim of this cross-sectional study was to evaluate the association between periodontal health and Chitinase 3-Like-1 (CHI3L1), a serological marker of cartilage damage, in patients with or without autoimmune and inflammatory rheumatic diseases (AIRD) and to assess its’ utility as biomarker of periodontal health. Methodology Participants were allocated into two groups: a cohort of patients with confirmed autoimmune inflammatory rheumatic diseases (AIRD), including rheumatoid arthritis (RA), ankylosing spondylitis (AxSpa), or psoriatic arthritis (PsA), and a control group consisting of individuals evaluated at our clinic for joint pain in whom AIRD was not confirmed. Participants were assigned to these groups retrospectively based on the presence or absence of AIRD. Consecutive patients referred by general practitioners for rheumatological examination to the rheumatology outpatient clinic of the 2nd Department of Internal Medicine St. Anne’s University Hospital in Brno, due to joint pain. Patients were screened for participation in the study and were approached for participation at their initial clinic visit, during which venous blood samples were collected from consenting patients. Subsequent examinations included an assessment by a dentist specialized in periodontology. Participants aged between 18 and 65 years were included. Exclusion criteria for both groups involved the presence of other systemic diseases that could influence the outcomes, such as diabetes or malignancies, as well as individuals unable or unwilling to provide informed consent. Data collection involved both rheumatological and periodontal assessments. The rheumatological examination included a detailed medical history, documenting symptom duration, family history, comorbidities, medication use, and smoking status. The clinical examination assessed the number of swollen and tender joints and subjective pain status using the Visual Analogue Scale (VAS) and the specific joints affected by the disease. Additionally, venous blood samples were collected for the measurement of rheumatoid factor (RF) in IgG, IgM, and IgA classes; anti-cyclic citrullinated peptide (anti-CCP) antibodies; anti-mutated citrullinated vimentin (anti-MCV) antibodies; C-reactive protein (CRP); and erythrocyte sedimentation rate (ESR). The periodontal assessment was standardized and performed by a single experienced dentist to ensure consistency in the evaluation. This assessment involved a detailed medical history, including oral hygiene habits and family history of dental/periodontal diseases. The clinical examination included the Community Periodontal Index of Treatment Needs (CPITN), Bleeding on Probing (BOP), Plaque Index (PI), Gingival Index (GI), and Clinical Attachment Loss (CAL), measured from the cement-enamel junction (CEJ). Panoramic X-ray (OPG) and bitewing (BW) radiographs were obtained to assess alveolar bone loss and overall periodontal health. As part of the biological sample collection, venous blood samples were also processed for molecular and biochemical analyses, with a focus on the quantification of CHI3L1, a serological marker of cartilage damage and tissue inflammation. The samples were centrifuged and stored at -80°C for subsequent analysis, using enzyme-linked immunosorbent assay (ELISA) techniques. Ethical approval for the study was obtained from the Institutional Review Board of St. Anne’s University Hospital, Brno (Reference Number: 64V/2022). The approval was granted on 12 October 2022 following review of all required study documents, including the study protocol (V2_300922), patient information sheet, and informed consent form (version_2022_09_30). Written informed consent was obtained from all participants prior to their inclusion in the study. Statistics Continuous variables were described using means and standard deviations (SD) or median values and ranges (min - max), while categorical variables were presented as frequencies and percentages. Data were examined for normality by the Shapiro-Wilk test. Continuous variables were compared between two groups with a two-sample t-test when the normality assumption was met; otherwise, the Mann-Whitney U test was used. Differences among the three groups were compared using Kruskal-Wallis ANOVA and Dunn’s post hoc test with adjustment using Hochberg corrections. For categorical variables, the chi-square test was used. The correlation between variables was measured by the Spearman rank correlation. A linear regression model was used to measure the association between the outcome variable (log (CHI3L1)) and explanatory variable PI together with adjusting variables age and sex. A p-value of < 0.05 was considered statistically significant. Statistical analyses were performed using R software, version 4.3.1 (R Core Team 2023, R Foundation for Statistical Computing, Vienna, Austria). Results A total of 49 subjects were included in the study. Each had their CH3L1 concentration measured, underwent rheumatological examination, and had a confirmed diagnosis of autoimmune rheumatic disease (AIRD; n = 14) or were designated as control subjects (n = 35), (Fig. 1 ). All subjects The mean age of the entire cohort was 49.0 years, with a predominance of female participants (73.5%). More than half of the subjects were non-smokers (69.4%). The baseline characteristics of each group are presented in Table 1 ; there was no difference between the AIRD and control groups (p > 0.05). All 49 subjects with complete data were included in the comparison of CHI3L1 levels across different groups. Patients with an AIRD diagnosis had a slightly higher median CH3L1 level (42.2 ng/ml) than control subjects (37.0 ng/ml); however, this difference was not statistically significant (p = 0.785), and there was notably higher variability among control subjects (Fig. 2 , Table 2 ). Table 1 Baseline characteristics of study groups Group AIRD Control p-value n 14 35 age [years] mean (SD) 45.6 (13.6) 50.3 (9.0) 0.163 Sex F (%) 11 (78.6) 25 (71.4) 0.878 M (%) 3 (21.4) 10 (28.6) Smoking status Never smoker 11 (78.6) 23 (65.7) 0.534 Ex-smoker 0 (0.0) 6 (17.1) 20 per day 1 (7.1) 2 (5.7) CHI3L1 levels were significantly higher in males (62.1 ng/ml) than females (36.4 ng/ml) (p = 0.008, Fig. 3 , Table 2 ). Table 2 CH3L1 comparisons Group p-value AIRD Control n 14 35 CH3L1 level [ng/ml] (median [min, max]) 42.2 [7.5, 83.5] 37.0 [9.8, 255.3] 0.785 Gender Male Female n 13 36 CH3L1 level [ng/ml] (median [min, max]) 62.1 [22.7, 255.3] 36.4 [7.5, 160.4] 0.008 AIRD Male Female n 3 11 CH3L1 level [ng/ml] (median [min, max]) 44.8 [27.3, 62.1] 41.8 [7.5, 83.5] 0.659 Control Male Female n 10 25 CH3L1 level [ng/ml] (median [min, max]) 95.7 [22.7, 255.3] 33.5 [9.8, 160.4] 0.011 A weak but statistically significant correlation was observed between age and CHI3L1 concentration (rS = 0.397; p = 0.005). Subgroup with dental examination Out of the 49 subjects, dental examination data was available for 36. No differences in baseline characteristics were found between the AIRD and control groups (Table 3 ). Table 3 Baseline characteristics of study groups for subgroup with dental examination Group AIRD Control p-value n 11 25 age [years] mean (SD) 45.6 (13.9) 51.1 (9.8) 0.176 Sex F (%) 8 (72.7) 18 (72.0) 1.000 M (%) 3 (27.3) 7 (28.0) Smoking status Never smoker 8 (72.7) 16 (64.0) 0.333 Ex-smoker 0 (0.0) 5 (20.0) 20 per day 1 (9.1) 2 (8.0) Porphyromonas gingivalis ND* 1 (9.1) 6 (24.0) neg 6 (54.5) 11 (44.0) 0.472 posit + 1 (9.1) 0 (0.0) posit ++ 0 (0.0) 1 (4.0) posit +++ 3 (27.3) 7 (28.0) * ND category was not included to test for differences in AIRD and control groups. Findings in CHI3L1 comparisons between study groups and gender were similar to results for the whole study population (Table 4 ). CHI3L1 levels differed significantly between PI (Periodontal Index) categories (p = 0.006). CHI3L1 concentration was significantly higher in subjects with PI in category 3 (median 109.6 ng/ml) than in those in category 1 with a median of 21.4 ng/ml (p = 0.006) or category 2 (median 37.4 ng/ml;p = 0.049; Fig. 4 , Table 4 ). Table 4 CH3L1 comparisons for subgroup with dental examination Group p-value AIRD Control n 11 25 CH3L1 level [ng/ml] (median [min, max]) 37.7 [7.5, 79.1] 38.6 [9.8, 255.3] 0.460 Gender Male Female n 10 26 CH3L1 level [ng/ml] (median [min, max]) 58.5 [22.7, 255.3] 36.4 [7.5, 160.4] 0.014 PI P1 P2 P3 n 9 16 11 CH3L1 level [ng/ml] (median [min, max]) 21.4 [7.5, 148.6] 37.4 [12.3, 160.4] 109.6 [18.8, 255.3] 0.006 PPD (Periodontal Probing Depth) was not correlated with CH3IL1 concentration (rS = 0.291; p = 0.085). The AIRD group showed higher values in all inflammatory variables compared to the control group. (Table 5 ) Table 5 Inflammatory variables in study groups for subgroup with dental examination Group AIRD Control p-value N 11 25 Swollen joints (median [min, max]) 4.00 [0.00, 20.00] 0.00 [0.00, 9.00] 0.014 Tender joints (median [min, max]) 4.00 [0.00, 20.00] 0.00 [0.00, 10.00] 0.017 VAS (median [min, max]) 50.00 [0.00, 80.00] 30.00 [0.00, 80.00] 0.061 CRP (median [min, max]) 2.80 [0.60, 51.80] 2.20 [0.00, 8.40] 0.503 FW (median [min, max]) 11.00 [4.00, 50.00] 11.00 [2.00, 29.00] 0.534 RF IgG (median [min, max]) 5.50 [0.90, 40.00] 3.40 [0.60, 46.00] 0.065 a RF IgA (median [min, max]) 4.30 [2.10, 63.00] 3.40 [1.00, 36.00] 0.213 a RF IgM (median [min, max]) 2.80 [1.20, 48.00] 1.50 [0.00, 19.00] 0.009 a a RF IgG, RF IgA a RF IgM was uknown for one subject. PI was the statistically significant predictor (p = 0.012) of CH3L1 in a linear regression adjusting for age and sex. The model indicates that for each unit increase in PI, the CH3L1 level increases by 62%. (Table 6 ) Table 6 Multiple linear regression for CH3L1 level β eβ e𝛽 CI p-value CH3L1 level [ng/ml] PI 0.48 1.62 1.12;2.34 0.012 Age [years] 0.01 1.01 0.99;1.04 0.330 Sex (M) 0.45 1.57 0.86;2.84 0.135 Discussion CHI3L1 levels correlated with the severity of periodontal disease, with higher concentrations observed in individuals with poorer oral health. These findings suggest that CHI3L1 is associated with periodontitis independently of the presence of AIRD in patients presenting with joint pain. Our study highlights a potential association between oral hygiene, as measured by the plaque index (PI), and levels of chitinase 3-like-1 protein (CHI3L1), a potential serological marker of cartilage degradation. The findings revealed that poor oral hygiene and elevated PI scores were significantly associated with increased CHI3L1 levels, suggesting that oral health may contribute to cartilage degradation. One of the strengths of our study is the elimination of the potential effect of DMARDs treatment on periodontal status; all the subjects were DMARDs naive. The most used group of biological DMARDs (anti-TNF alpha monoclonal antibodies) have been shown to improve periodontal health. ( 10 ) All the subjects in our study were newly diagnosed with AIRD. Interestingly, no significant differences in CHI3L1 levels were observed between patients with autoimmune rheumatic diseases (AIRD) and healthy controls. One plausible explanation could be related to the study’s sample size and composition. Given the limited number of subjects, variability in individual health behaviours, disease severity, and treatment history within the AIRD group may have masked potential differences. Another possible explanation is that our control group consisted of individuals who were examined due to joint issues, and thus, it is possible that these patients had varying degrees of osteoarthritis. Another explanation is the unequal proportion of smokers in the control group. Future studies with larger and more homogenous sample sizes are needed to ascertain if CHI3L1 levels consistently differentiate AIRD patients from control subjects. Alternatively, elevated CHI3L1 levels in individuals with poorer oral hygiene could reflect the secondary effects of joint damage on oral tissues, such as reduced ability to maintain oral hygiene due to physical limitations or pain. However, previous studies showed just a partial effect of poorer oral hygiene in the group of RA patients on their higher risk of periodontitis development. ( 11 ) Since all our patients were examined by a rheumatologist for the first time in their lives and the maximum inclusion age was 65 years, we do not expect this to be the case in our patient cohort. Although CHI3L1 levels were higher in patients with poorer periodontal hygiene, as indicated by higher Plaque Index (PI) scores, the relationship between cartilage damage—a hallmark of systemic rheumatic disease—and oral hygiene is complex. Functional limitations from cartilage damage may impair oral care, indirectly worsening periodontal status, but this hypothesis requires validation through additional biomarkers. The observed association between CHI3L1 and PI suggests a potential link between systemic inflammation and periodontal health; however, it remains unclear whether other indicators, such as gingival index or clinical attachment levels, show similar correlations. Broader assessment of periodontal parameters, alongside longitudinal studies, could clarify causal relationships and the impact of improved oral hygiene on systemic markers like CHI3L1 in AIRD and related conditions. Given CHI3L1’s known involvement in tissue remodelling and inflammation, monitoring CHI3L1 in patients with compromised oral health—especially those with AIRD—could be critical for early intervention. However, the study has several limitations, including the relatively small sample size, the unequal distribution of participants between the AIRD and control groups, and the imbalance in the proportion of smokers, which may act as an important confounding factor. Periodontitis and Autoimmune Disease Development A growing body of evidence suggests that periodontitis may play a significant role in the development and progression of rheumatoid arthritis (RA). The main periopathogens (bacterial species found in sites affected by periodontitis) involved in this process include P. gingivalis and A. actinomycetemcomitans. P. gingivalis could citrullinate host proteins, a post-translational modification that is a key trigger for the autoimmune response seen in RA. This citrullination process leads to the formation of anti-citrullinated protein antibodies (ACPA), which are implicated in the pathogenesis of RA. ( 12 ) Recent meta-analyses have reinforced the hypothesis that periodontitis is not only associated with RA but may also serve as a risk factor for its development. This meta-analysis demonstrates that patients with periodontitis have a substantially increased risk of developing rheumatoid arthritis, with an overall 69% higher risk compared to healthy controls. Stratified analyses further suggest that periodontitis is particularly associated with incident RA and with patients experiencing longer disease duration, supporting the concept that periodontal inflammation may contribute to the initiation and perpetuation of RA. ( 13 ) The relationship between periodontitis (PD) and rheumatoid arthritis (RA) appears to be bidirectional. Individuals with RA are at an increased risk of developing PD, and conversely, PD may elevate the risk of developing RA. This bidirectional association is attributed to shared inflammatory pathways and immune system dysregulation. Interestingly, the relationship between PD and RA varies across RA subtypes. ACPA-positive RA may have a stronger association with PD, potentially due to shared pathogenic mechanisms involving citrullination processes induced by periodontal pathogens like P. gingivalis. ( 14 ) Furthermore, the exact role of ACPA antibodies in mediating this relationship is still under investigation. ACPA positivity often precedes clinical arthritis by several years, indicating that the immune response to citrullinated proteins may be an early event in RA pathogenesis, potentially triggered or exacerbated by oral bacteria. ( 15 ) Recent research has further explored the connection between oral health and systemic disease by examining episodes of oral bacteraemia in RA patients. These episodes, which involve the translocation of oral bacteria into the bloodstream, appear to trigger systemic immune responses, including the production of ACPA antibodies. These findings suggest that oral bacteria, particularly those that undergo citrullination in the oral cavity, may contribute to systemic inflammation and disease relapse in RA patients. ( 16 ) Although growing evidence implicates oral pathogens, citrullination processes, and systemic immune activation in this association, the precise mechanisms linking periodontitis to RA development remain unclear. Consistent with these uncertainties, the ESPERA randomized controlled trial demonstrated that although periodontal treatment significantly improved periodontal health in RA patients, it did not translate into measurable changes in RA disease activity or overall quality of life. ( 17 ) Taken together, these findings highlight a complex, potentially bidirectional relationship between periodontitis and rheumatoid arthritis, in which oral inflammation may contribute to RA onset and progression, yet clinical interventions targeting periodontal disease alone may not be sufficient to modify systemic disease activity. Given the established role of systemic inflammation in the pathogenesis of RA and its association with periodontal disease, attention has turned to molecular mediators such as CHI3L1, which may link oral and systemic inflammatory processes. In the context of oral inflammation, CHI3L1 levels have been shown to increase stimulation with tumor necrosis factor alpha (TNF-α) in human oral epithelial cells, specifically in the HSC3 and HSC4 cell lines. Patient samples have confirmed higher CHI3L1 expression in inflamed lesions, indicating a key role for CHI3L1 in oral inflammation and the development of conditions like periodontitis. ( 18 ) This aligns with our study's findings suggesting a potential link between CHI3L1 and periodontal disease, especially in patients with systemic inflammatory conditions. In contrast to the findings reported by Sanfilippo et al. (2019), ( 19 ) our study observed higher serum CHI3L1 levels in male participants. One possible explanation for this discrepancy is that circulating CHI3L1 levels may not directly reflect its expression in the brain, highlighting tissue-specific differences in CHI3L1 regulation. Additionally, genetic variability in the CHI3L1 gene may contribute to differences in serum CHI3L1 levels. Nielsen et al. (2011) identified a significant association between the g.-131 (C > G) polymorphism (rs4950928) in the CHI3L1 promoter region and serum YKL-40 concentrations in both rheumatoid arthritis patients and healthy controls; however, they did not observe sex-related differences, in contrast to our findings. This suggests that additional, yet unidentified factors may contribute to the higher serum CHI3L1 levels in males in our cohort. ( 20 ) In summary, periodontitis and rheumatoid arthritis appear to share a complex, bidirectional relationship. The evidence suggests that oral bacteria, such as P. gingivalis, contribute to the onset and progression of RA through mechanisms such as citrullination, which leads to the formation of ACPA antibodies. In turn, RA patients are at increased risk for developing periodontal disease, which may exacerbate systemic inflammation. The findings underscore the importance of monitoring oral health in patients with autoimmune diseases, as improving periodontal status may help mitigate systemic inflammation and potentially improve disease outcomes. Given the role of CHI3L1 in both inflammation and tissue remodelling, further research into its association with oral health could provide valuable insights into the mechanisms linking periodontitis and systemic inflammatory conditions like RA. Early intervention and treatment of periodontitis in RA patients may therefore offer therapeutic potential for reducing disease activity and improving quality of life. Conclusion Our findings underscore a potential connection between oral health and cartilage degradation in patients with AIRD or with osteoarthritis. While no significant differences in CHI3L1 levels were found between AIRD patients and controls, higher plaque index (PI) scores were associated with significantly increased CHI3L1 levels. This observation supports the hypothesis that oral hygiene may influence systemic inflammatory processes, leading to cartilage damage. From a clinical perspective, these findings emphasize the importance of preventing and managing periodontitis as a potential strategy for mitigating systemic inflammation in patients with AIRD. However, further research is warranted to validate these results, particularly through longitudinal and interventional studies. Such research could clarify whether improving oral hygiene and treating periodontitis leads to reductions in systemic inflammatory markers, including CHI3L1, and contribute to better disease management in AIRD patients. Abbreviations AIRD – autoimmune inflammatory rheumatic diseases RA – rheumatoid arthritis PsA – psoriatic arthritis AxSpA – axial spondyloarthritis OA – osteoarthritis SLE – systemic lupus erythematosus PD – periodontitis ACPAs – anti-citrullinated protein antibodies DMARDs – disease-modifying antirheumatic drugs CHI3L1 – chitinase 3-like 1 VAS – Visual Analogue Scale RF – rheumatoid factor anti-CCP – anti-cyclic citrullinated peptide antibodies anti-MCV – anti-mutated citrullinated vimentin antibodies CRP – C-reactive protein ESR – erythrocyte sedimentation rate CPITN – Community Periodontal Index of Treatment Needs BOP – Bleeding on Probing PI – Plaque Index GI – Gingival Index CAL – Clinical Attachment Loss CEJ – cement–enamel junction OPG – orthopantomogram BW – bitewing radiograph ELISA – enzyme-linked immunosorbent assay SD – standard deviation anti-TNF – anti–tumor necrosis factor alpha VAS – Visual Analogue Scale RF IgG – rheumatoid factor immunoglobulin G RF IgA – rheumatoid factor immunoglobulin A RF IgM – rheumatoid factor immunoglobulin M Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of St. Anne’s University Hospital in Brno (Reference Number: 64V/2022). The approval was granted on 12 October 2022 following review of all required study documents, including the study protocol (V2_300922), patient information sheet, and informed consent form (version_2022_09_30). All participants were informed about the purpose and procedures of the study and provided written informed consent prior to enrolment. All procedures were conducted in accordance with the Declaration of Helsinki and relevant national guidelines. Consent for publication All participants provided written informed consent allowing anonymized data to be used for scientific publication. No identifying information is included in this manuscript. Availability of data and materials The datasets generated and analysed during the current study are available from the corresponding author on reasonable request. Due to ethical and privacy restrictions, individual-level clinical data cannot be made publicly available. Competing interests The authors declare that they have no competing interests. Funding This study was supported by St. Anne's University Hospital in Brno Support for Internal Pilot Research Projects (grant no. FNDN_IP23IPV02EXA_PN and grant no. FNDN_IP24IPV02EXA_PN) and by project MUNI/A/1768/2024. Authors’ contributions Adam Lukac – principal investigator; corresponding author, conceptualisation, study design, patient recruitment, data collection, data interpretation, and manuscript drafting. 2nd Department of Internal Medicine, Faculty of Medicine of Masaryk University and St. Anne´s University Hospital in Brno, https://orcid.org/0000-0002-2946-1463 Eva Buchalova – sub-investigator; clinical examinations, periodontal assessments, data collection. Clinic of Stomatology, Faculty of Medicine, Masaryk University Lucie Buresova, St. Anne’s University Hospital in Brno, Center for International Clinical Research, Faculty of Medicine of Masaryk University, https://orcid.org/0000-0003-4193-0194 Jana Sistkova, Department of Pathophysiology Faculty of Medicine, Masaryk University, Brno, https://orcid.org/0000-0001-6378-1631 Petr Němec, 2nd Department of Internal Medicine, Faculty of Medicine of Masaryk University and St. Anne´s University Hospital in Brno, https://orcid.org/0000-0003-2287-7615 Monika Pavkova Goldbergova, Department of Pathophysiology Faculty of Medicine, Masaryk University, Brno, https://orcid.org/0000-0002-3471-8702 Lydie Izakovicova Holla) – senior author; critical revision of the manuscript for important intellectual content; Clinic of Stomatology, Faculty of Medicine, Masaryk University; ORCID: https://orcid.org/0000-0002-7610-8929 All authors read and approved the final manuscript. Acknowledgements This study was supported by St. Anne's University Hospital in Brno Support for Internal Pilot Research Projects (grant no. FNDN_IP23IPV02EXA_PN and grant no. FNDN_IP24IPV02EXA_PN) and by project MUNI/A/1768/2024. References den Hollander NK, Verstappen M, Huizinga TW, van der Helm-van Mil A. Management of contemporary early undifferentiated arthritis: data on EULAR's recommendation on the risk of persistent disease. Ann Rheum Dis. 2022;81(5):740–1. http://dx.doi.org/10.1136/annrheumdis-2021-221821 Slots J. Periodontitis: Facts, fallacies, and the future. Periodontol 2000. 2017;75(1):7–23. http://dx.doi.org/10.1111/prd.12221 De Pablo P, Dietrich T, McAlindon TE. Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. J Rheumatol. 2008;35(1):70–6. (no DOI available) Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ, Beck J, et al. Prevalence of periodontitis in adults in the United States: 2009 and 2010. 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Rheumatoid arthritis-associated mechanisms of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. J Clin Med. 2019;8(9):1309. http://dx.doi.org/10.3390/jcm8091309 Qiao Y, Wang Z, Li Y, Han Y, Zhou Y, Cao X. Rheumatoid arthritis risk in periodontitis patients: A systematic review and meta-analysis. Joint Bone Spine. 2020;87(6):556–64. http://dx.doi.org/10.1016/j.jbspin.2020.04.024 Fang, H., Lin, J., Qiu, Y., Cheng, Z., & Chen, W. (2025). Epidemiology and pathogenesis of the link between rheumatoid arthritis and periodontitis. Journal of Zhejiang University. Science. B, 26(5), 448–460. https://doi.org/10.1631/jzus.B2300519 Khatri S, Hansen J, Astakhova K. Antibodies to synthetic citrullinated peptide epitope correlate with disease activity and flares in rheumatoid arthritis. PLoS One. 2020;15(4):e0232010. http://dx.doi.org/10.1371/journal.pone.0232010 Brewer RC, Lanz TV, Hale CR, Sepich-Poore GD, Martino C, Swafford AD, Carroll TS, et al. Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Sci Transl Med. 2023;15(684):eabq8476. http://dx.doi.org/10.1126/scitranslmed.abq8476 Monsarrat P, De Grado GF, Constantin A, et al. The effect of periodontal treatment on patients with rheumatoid arthritis: The ESPERA randomised controlled trial. Joint Bone Spine. 2019;86(4):439–40. http://dx.doi.org/10.1016/j.jbspin.2019.02.006 Teratani Y. Chitinase 3-Like-1 Expression Is Upregulated Under Inflammatory Conditions in Human Oral Epithelial Cells. Kurume Med J. 2023;68(3–4):221–8. http://dx.doi.org/10.2739/kurumemedj.MS6834014 Sanfilippo, C., Castrogiovanni, P., Imbesi, R., Kazakowa, M., Musumeci, G., Blennow, K., Zetterberg, H., & Di Rosa, M. (2019). Sex difference in CHI3L1 expression levels in human brain aging and in Alzheimer's disease. Brain research, 1720, 146305. https://doi.org/10.1016/j.brainres.2019.146305 Nielsen KR, Steffensen R, Boegsted M, Baech J, Lundbye-Christensen S, Hetland ML, et al. Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects. Arthritis Res Ther. 2011;13(3):R109. http://dx.doi.org/10.1186/ar3391 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8305752","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589395419,"identity":"c34b5ebf-4ab6-4590-b9bc-fabde58fceef","order_by":0,"name":"Adam Lukac","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYFCCBCAuYDBgYGA+8IEELQYgLWyJM0jVwmNInBb+9uSnGxgMDhvzt5/52FzYVifPwH78AV4tEmeemd0AajGTOJO7sXlm22HDBp6EBPzW3EgAa7FhuMG7/TFv2wHGBgmGA3h1yN9I/wbWIn+D52Ezb1udfYMEYwNeLQY3ciAOM7jBwwjUwpzYIMGM312GZ96U3UgwSDc2PJNm2Mxz7nByG08afi1yx9O33fhQYW047/jhh808ZXW2/YRCDAwSkDlshNWPglEwCkbBKCAEABC7R+M7rZL+AAAAAElFTkSuQmCC","orcid":"","institution":"St. Anne´s University Hospital in Brno","correspondingAuthor":true,"prefix":"","firstName":"Adam","middleName":"","lastName":"Lukac","suffix":""},{"id":589395420,"identity":"a52e118f-364d-4aea-a072-ceb0e10eab18","order_by":1,"name":"Eva Buchalova","email":"","orcid":"","institution":"St. Anne´s University Hospital in Brno","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Buchalova","suffix":""},{"id":589395421,"identity":"fc07c72a-7eb0-4743-af4c-cd0d6a8e276f","order_by":2,"name":"Jana Sistkova","email":"","orcid":"","institution":"Masaryk University","correspondingAuthor":false,"prefix":"","firstName":"Jana","middleName":"","lastName":"Sistkova","suffix":""},{"id":589395422,"identity":"130230e5-a4eb-49cc-a6a1-a6a6196c03af","order_by":3,"name":"Lucie Buresova","email":"","orcid":"","institution":"St. Anne´s University Hospital in Brno","correspondingAuthor":false,"prefix":"","firstName":"Lucie","middleName":"","lastName":"Buresova","suffix":""},{"id":589395423,"identity":"07966db1-b682-46f0-ba79-56e777b6d16b","order_by":4,"name":"Petr Nemec","email":"","orcid":"","institution":"St. Anne´s University Hospital in Brno","correspondingAuthor":false,"prefix":"","firstName":"Petr","middleName":"","lastName":"Nemec","suffix":""},{"id":589395424,"identity":"fb43cd5e-b8be-41c4-8e81-27ecd885145b","order_by":5,"name":"Monika Pavkova Goldbergova","email":"","orcid":"","institution":"Masaryk University","correspondingAuthor":false,"prefix":"","firstName":"Monika","middleName":"Pavkova","lastName":"Goldbergova","suffix":""},{"id":589395426,"identity":"3593a7d5-30e2-4f80-8788-a4a47252b44d","order_by":6,"name":"Lydie Izakovicova Holla","email":"","orcid":"","institution":"St. Anne´s University Hospital in Brno","correspondingAuthor":false,"prefix":"","firstName":"Lydie","middleName":"Izakovicova","lastName":"Holla","suffix":""}],"badges":[],"createdAt":"2025-12-08 09:49:48","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8305752/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8305752/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102596649,"identity":"556db41b-c741-4fdf-a904-a903197d3de2","added_by":"auto","created_at":"2026-02-13 12:23:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":142854,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart summarizing the reasons for exclusion from the final analysis\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8305752/v1/048af236d94ca52fa7728530.png"},{"id":102596650,"identity":"a88c85b4-4875-4111-aa8e-418173b71017","added_by":"auto","created_at":"2026-02-13 12:23:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26687,"visible":true,"origin":"","legend":"\u003cp\u003eCH3L1 levels in AIRD and control group\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8305752/v1/87831cdf35041ded30f106f5.png"},{"id":102596647,"identity":"c43393a2-5872-408b-9949-271bdbfb4911","added_by":"auto","created_at":"2026-02-13 12:23:03","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":25227,"visible":true,"origin":"","legend":"\u003cp\u003eCH3L1 levels in males and females\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8305752/v1/57fa76de92843d9bd1077ad8.png"},{"id":102596651,"identity":"2457df0e-28e2-45eb-93fc-a1f8c462550c","added_by":"auto","created_at":"2026-02-13 12:23:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":28143,"visible":true,"origin":"","legend":"\u003cp\u003eCH3L1 levels in different PI grades\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8305752/v1/a6ac0542041fbef33c9cdd01.png"},{"id":102747446,"identity":"165f6a88-85d9-4cb2-9958-188aed5285bf","added_by":"auto","created_at":"2026-02-16 09:04:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1165087,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8305752/v1/448a90b5-6f9f-4dd0-b685-1e1b06e2dc80.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Periodontal Health and Chitinase 3-Like-1 Levels in Autoimmune Rheumatic Diseases and Osteoarthritis ","fulltext":[{"header":"Background","content":"\u003cp\u003eEarly presentations of autoimmune inflammatory rheumatic diseases (AIRD) often manifest as joint inflammation without an immediately identifiable etiology. At this stage, the differential diagnosis spans a broad spectrum of disorders, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (AxSpA), osteoarthritis with inflammatory features (OA), and systemic connective tissue diseases such as systemic lupus erythematosus (SLE). (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Understanding this diagnostic uncertainty is critical for guiding early management and preventing long-term disease progression.\u003c/p\u003e \u003cp\u003eAmong these diseases, the connection between periodontitis (PD) and rheumatoid arthritis is the most evident. Both diseases exhibit certain similar features in their pathogenic processes and a similar ability to cause bone destruction at sites of inflammation. Additionally, both diseases share some common risk factors, including smoking, obesity, socioeconomic status, and genetic factors (HLA-DRB1).\u003c/p\u003e \u003cp\u003ePeriodontitis is an inflammatory disease characterized by the pathological loss of periodontal ligaments and alveolar bone. It is a multifactorial disease involving a dynamic interaction between pathogenic microorganisms and a destructive immune response. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) PD is a prevalent disease affecting up to 47% of the adult population and leads to gum bleeding with the translocation of oral bacteria into the bloodstream. In its advanced stages, PD leads to tooth loss and a reduction in quality of life. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) PD is more common in patients with rheumatoid arthritis (RA), especially in RA with anti-citrullinated protein antibodies (ACPAs). (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Periodontal therapy is locally effective in patients with rheumatoid arthritis and, in those with severe periodontitis, is associated with reductions in RA disease activity and ACPA levels, suggesting that PD may trigger systemic inflammatory pathways relevant to ongoing joint inflammation. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Periodontitis associates with rheumatoid arthritis from early disease stages. RA treatments outside some biological DMARDs are ineffective in treatment of periodontitis which highlight the unmet need to identify RA at risk of periodontitis early and to prioritise them for specialist periodontal therapies. (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) The connection between periodontitis and other common diseases causing autoimmune arthritis (e.g. SLE, PsA, AxSpa) remains largely elusive with some suggestions of higher incidence of periodontitis in patients with SLE, and direct correlation with disease activity. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eChitinase 3-Like-1 (CHI3L1) features in pathogenies of both RA and periodontitis. This cartilage-derived protein is increasingly recognized in joint damage. Elevated CHI3L1 levels have also been observed in patients with hip OA, further underscoring its relevance as an indicator of cartilage damage. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe aim of this cross-sectional study was to evaluate the association between periodontal health and Chitinase 3-Like-1 (CHI3L1), a serological marker of cartilage damage, in patients with or without autoimmune and inflammatory rheumatic diseases (AIRD) and to assess its\u0026rsquo; utility as biomarker of periodontal health.\u003c/p\u003e"},{"header":"Methodology","content":"\u003cp\u003eParticipants were allocated into two groups: a cohort of patients with confirmed autoimmune inflammatory rheumatic diseases (AIRD), including rheumatoid arthritis (RA), ankylosing spondylitis (AxSpa), or psoriatic arthritis (PsA), and a control group consisting of individuals evaluated at our clinic for joint pain in whom AIRD was not confirmed. Participants were assigned to these groups retrospectively based on the presence or absence of AIRD. Consecutive patients referred by general practitioners for rheumatological examination to the rheumatology outpatient clinic of the 2nd Department of Internal Medicine St. Anne\u0026rsquo;s University Hospital in Brno, due to joint pain. Patients were screened for participation in the study and were approached for participation at their initial clinic visit, during which venous blood samples were collected from consenting patients. Subsequent examinations included an assessment by a dentist specialized in periodontology. Participants aged between 18 and 65 years were included. Exclusion criteria for both groups involved the presence of other systemic diseases that could influence the outcomes, such as diabetes or malignancies, as well as individuals unable or unwilling to provide informed consent.\u003c/p\u003e\n\u003cp\u003eData collection involved both rheumatological and periodontal assessments. The rheumatological examination included a detailed medical history, documenting symptom duration, family history, comorbidities, medication use, and smoking status. The clinical examination assessed the number of swollen and tender joints and subjective pain status using the Visual Analogue Scale (VAS) and the specific joints affected by the disease. Additionally, venous blood samples were collected for the measurement of rheumatoid factor (RF) in IgG, IgM, and IgA classes; anti-cyclic citrullinated peptide (anti-CCP) antibodies; anti-mutated citrullinated vimentin (anti-MCV) antibodies; C-reactive protein (CRP); and erythrocyte sedimentation rate (ESR).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe periodontal assessment was standardized and performed by a single experienced dentist to ensure consistency in the evaluation. This assessment involved a detailed medical history, including oral hygiene habits and family history of dental/periodontal diseases. The clinical examination included the Community Periodontal Index of Treatment Needs (CPITN), Bleeding on Probing (BOP), Plaque Index (PI), Gingival Index (GI), and Clinical Attachment Loss (CAL), measured from the cement-enamel junction (CEJ). Panoramic X-ray (OPG) and bitewing (BW) radiographs were obtained to assess alveolar bone loss and overall periodontal health.\u003c/p\u003e\n\u003cp\u003eAs part of the biological sample collection, venous blood samples were also processed for molecular and biochemical analyses, with a focus on the quantification of CHI3L1, a serological marker of cartilage damage and tissue inflammation. The samples were centrifuged and stored at -80\u0026deg;C for subsequent analysis, using enzyme-linked immunosorbent assay (ELISA) techniques.\u003c/p\u003e\n\u003cp\u003eEthical approval for the study was obtained from the Institutional Review Board of St. Anne\u0026rsquo;s University Hospital, Brno (Reference Number: 64V/2022). The approval was granted on 12 October 2022 following review of all required study documents, including the study protocol (V2_300922), patient information sheet, and informed consent form (version_2022_09_30). Written informed consent was obtained from all participants prior to their inclusion in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were described using means and standard deviations (SD) or median values and ranges (min - max), while categorical variables were presented as frequencies and percentages. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData were examined for normality by the Shapiro-Wilk test. Continuous variables were compared between two groups with a two-sample t-test when the normality assumption was met; otherwise, the Mann-Whitney U test was used. Differences among the three groups were compared using Kruskal-Wallis ANOVA and Dunn\u0026rsquo;s post hoc test with adjustment using Hochberg corrections. For categorical variables, the chi-square test was used.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe correlation between variables was measured by the Spearman rank correlation. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA linear regression model was used to measure the association between the outcome variable (log (CHI3L1)) and explanatory variable PI together with adjusting variables age and sex.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA p-value of \u0026lt; 0.05 was considered statistically significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analyses were performed using R software, version 4.3.1 (R Core Team 2023, R Foundation for Statistical Computing, Vienna, Austria).\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 49 subjects were included in the study. Each had their CH3L1 concentration measured, underwent rheumatological examination, and had a confirmed diagnosis of autoimmune rheumatic disease (AIRD; n\u0026thinsp;=\u0026thinsp;14) or were designated as control subjects (n\u0026thinsp;=\u0026thinsp;35), (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eAll subjects\u003c/h3\u003e\n\u003cp\u003eThe mean age of the entire cohort was 49.0 years, with a predominance of female participants (73.5%). More than half of the subjects were non-smokers (69.4%).\u003c/p\u003e \u003cp\u003eThe baseline characteristics of each group are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e; there was no difference between the AIRD and control groups (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eAll 49 subjects with complete data were included in the comparison of CHI3L1 levels across different groups. Patients with an AIRD diagnosis had a slightly higher median CH3L1 level (42.2 ng/ml) than control subjects (37.0 ng/ml); however, this difference was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.785), and there was notably higher variability among control subjects (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of study groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAIRD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eage [years]\u003c/b\u003e\u003c/p\u003e \u003cp\u003emean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.6 (13.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.3 (9.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003cp\u003eF (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (78.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (71.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.878\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (28.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (78.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (65.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.534\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEx-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;10 per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u0026ndash;20 per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;20 per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (7.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (5.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCHI3L1 levels were significantly higher in males (62.1 ng/ml) than females (36.4 ng/ml) (p\u0026thinsp;=\u0026thinsp;0.008, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCH3L1 comparisons\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAIRD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCH3L1 level [ng/ml] (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.2\u003c/p\u003e \u003cp\u003e[7.5, 83.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.0\u003c/p\u003e \u003cp\u003e[9.8, 255.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.785\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCH3L1 level [ng/ml] (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.1\u003c/p\u003e \u003cp\u003e[22.7, 255.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.4\u003c/p\u003e \u003cp\u003e[7.5, 160.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.008\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eAIRD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCH3L1 level [ng/ml] (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44.8\u003c/p\u003e \u003cp\u003e[27.3, 62.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.8\u003c/p\u003e \u003cp\u003e[7.5, 83.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.659\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eControl\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCH3L1 level [ng/ml] (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95.7\u003c/p\u003e \u003cp\u003e[22.7, 255.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.5\u003c/p\u003e \u003cp\u003e[9.8, 160.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eA weak but statistically significant correlation was observed between age and CHI3L1 concentration (rS\u0026thinsp;=\u0026thinsp;0.397; p\u0026thinsp;=\u0026thinsp;0.005).\u003c/p\u003e\n\u003ch3\u003eSubgroup with dental examination\u003c/h3\u003e\n\u003cp\u003eOut of the 49 subjects, dental examination data was available for 36. No differences in baseline characteristics were found between the AIRD and control groups (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of study groups for subgroup with dental examination\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAIRD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eage [years]\u003c/b\u003e\u003c/p\u003e \u003cp\u003emean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.6 (13.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.1 (9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eF (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (72.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (72.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (72.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (64.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEx-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;10 per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u0026ndash;20 per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;20 per day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePorphyromonas gingivalis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eND*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eneg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (54.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (44.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.472\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eposit +\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (9.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eposit ++\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eposit +++\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (27.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e* ND category was not included to test for differences in AIRD and control groups.\u003c/p\u003e \u003cp\u003eFindings in CHI3L1 comparisons between study groups and gender were similar to results for the whole study population (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). CHI3L1 levels differed significantly between PI (Periodontal Index) categories (p\u0026thinsp;=\u0026thinsp;0.006). CHI3L1 concentration was significantly higher in subjects with PI in category 3 (median 109.6 ng/ml) than in those in category 1 with a median of 21.4 ng/ml (p\u0026thinsp;=\u0026thinsp;0.006) or category 2 (median 37.4 ng/ml;p\u0026thinsp;=\u0026thinsp;0.049; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCH3L1 comparisons for subgroup with dental examination\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAIRD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCH3L1 level [ng/ml] (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e37.7\u003c/p\u003e \u003cp\u003e[7.5, 79.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e38.6\u003c/p\u003e \u003cp\u003e[9.8, 255.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.460\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eGender\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003eMale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCH3L1 level [ng/ml] (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e58.5\u003c/p\u003e \u003cp\u003e[22.7, 255.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e36.4\u003c/p\u003e \u003cp\u003e[7.5, 160.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePI\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eP1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cb\u003eP2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eP3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003en\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCH3L1 level [ng/ml] (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.4\u003c/p\u003e \u003cp\u003e[7.5, 148.6]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e37.4\u003c/p\u003e \u003cp\u003e[12.3, 160.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e109.6\u003c/p\u003e \u003cp\u003e[18.8, 255.3]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003ePPD (Periodontal Probing Depth) was not correlated with CH3IL1 concentration (rS\u0026thinsp;=\u0026thinsp;0.291; p\u0026thinsp;=\u0026thinsp;0.085).\u003c/p\u003e \u003cp\u003eThe AIRD group showed higher values in all inflammatory variables compared to the control group. (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInflammatory variables in study groups for subgroup with dental examination\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAIRD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSwollen joints (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.00 [0.00, 20.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00 [0.00, 9.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTender joints (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.00 [0.00, 20.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.00 [0.00, 10.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.017\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVAS (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.00 [0.00, 80.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.00 [0.00, 80.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRP (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.80 [0.60, 51.80]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.20 [0.00, 8.40]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.503\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFW (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.00 [4.00, 50.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.00 [2.00, 29.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.534\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRF IgG (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.50 [0.90, 40.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.40 [0.60, 46.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.065 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRF IgA (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.30 [2.10, 63.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.40 [1.00, 36.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.213 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRF IgM (median [min, max])\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.80 [1.20, 48.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.50 [0.00, 19.00]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003eRF IgG, RF IgA a RF IgM was uknown for one subject.\u003c/p\u003e \u003cp\u003ePI was the statistically significant predictor (p\u0026thinsp;=\u0026thinsp;0.012) of CH3L1 in a linear regression adjusting for age and sex. The model indicates that for each unit increase in PI, the CH3L1 level increases by 62%. (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultiple linear regression for CH3L1 level\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eβ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eeβ\u003cem\u003ee\u0026#120573;\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eCH3L1 level [ng/ml]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.12;2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge [years]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99;1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.330\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.86;2.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.135\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCHI3L1 levels correlated with the severity of periodontal disease, with higher concentrations observed in individuals with poorer oral health. These findings suggest that CHI3L1 is associated with periodontitis independently of the presence of AIRD in patients presenting with joint pain. Our study highlights a potential association between oral hygiene, as measured by the plaque index (PI), and levels of chitinase 3-like-1 protein (CHI3L1), a potential serological marker of cartilage degradation. The findings revealed that poor oral hygiene and elevated PI scores were significantly associated with increased CHI3L1 levels, suggesting that oral health may contribute to cartilage degradation. One of the strengths of our study is the elimination of the potential effect of DMARDs treatment on periodontal status; all the subjects were DMARDs naive. The most used group of biological DMARDs (anti-TNF alpha monoclonal antibodies) have been shown to improve periodontal health. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) All the subjects in our study were newly diagnosed with AIRD.\u003c/p\u003e \u003cp\u003eInterestingly, no significant differences in CHI3L1 levels were observed between patients with autoimmune rheumatic diseases (AIRD) and healthy controls. One plausible explanation could be related to the study\u0026rsquo;s sample size and composition. Given the limited number of subjects, variability in individual health behaviours, disease severity, and treatment history within the AIRD group may have masked potential differences. Another possible explanation is that our control group consisted of individuals who were examined due to joint issues, and thus, it is possible that these patients had varying degrees of osteoarthritis. Another explanation is the unequal proportion of smokers in the control group. Future studies with larger and more homogenous sample sizes are needed to ascertain if CHI3L1 levels consistently differentiate AIRD patients from control subjects. Alternatively, elevated CHI3L1 levels in individuals with poorer oral hygiene could reflect the secondary effects of joint damage on oral tissues, such as reduced ability to maintain oral hygiene due to physical limitations or pain. However, previous studies showed just a partial effect of poorer oral hygiene in the group of RA patients on their higher risk of periodontitis development. (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) Since all our patients were examined by a rheumatologist for the first time in their lives and the maximum inclusion age was 65 years, we do not expect this to be the case in our patient cohort.\u003c/p\u003e \u003cp\u003eAlthough CHI3L1 levels were higher in patients with poorer periodontal hygiene, as indicated by higher Plaque Index (PI) scores, the relationship between cartilage damage\u0026mdash;a hallmark of systemic rheumatic disease\u0026mdash;and oral hygiene is complex. Functional limitations from cartilage damage may impair oral care, indirectly worsening periodontal status, but this hypothesis requires validation through additional biomarkers. The observed association between CHI3L1 and PI suggests a potential link between systemic inflammation and periodontal health; however, it remains unclear whether other indicators, such as gingival index or clinical attachment levels, show similar correlations. Broader assessment of periodontal parameters, alongside longitudinal studies, could clarify causal relationships and the impact of improved oral hygiene on systemic markers like CHI3L1 in AIRD and related conditions. Given CHI3L1\u0026rsquo;s known involvement in tissue remodelling and inflammation, monitoring CHI3L1 in patients with compromised oral health\u0026mdash;especially those with AIRD\u0026mdash;could be critical for early intervention. However, the study has several limitations, including the relatively small sample size, the unequal distribution of participants between the AIRD and control groups, and the imbalance in the proportion of smokers, which may act as an important confounding factor.\u003c/p\u003e \u003cp\u003ePeriodontitis and Autoimmune Disease Development\u003c/p\u003e \u003cp\u003eA growing body of evidence suggests that periodontitis may play a significant role in the development and progression of rheumatoid arthritis (RA). The main periopathogens (bacterial species found in sites affected by periodontitis) involved in this process include P. gingivalis and A. actinomycetemcomitans. P. gingivalis could citrullinate host proteins, a post-translational modification that is a key trigger for the autoimmune response seen in RA. This citrullination process leads to the formation of anti-citrullinated protein antibodies (ACPA), which are implicated in the pathogenesis of RA. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eRecent meta-analyses have reinforced the hypothesis that periodontitis is not only associated with RA but may also serve as a risk factor for its development. This meta-analysis demonstrates that patients with periodontitis have a substantially increased risk of developing rheumatoid arthritis, with an overall 69% higher risk compared to healthy controls. Stratified analyses further suggest that periodontitis is particularly associated with incident RA and with patients experiencing longer disease duration, supporting the concept that periodontal inflammation may contribute to the initiation and perpetuation of RA. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) The relationship between periodontitis (PD) and rheumatoid arthritis (RA) appears to be bidirectional. Individuals with RA are at an increased risk of developing PD, and conversely, PD may elevate the risk of developing RA. This bidirectional association is attributed to shared inflammatory pathways and immune system dysregulation. Interestingly, the relationship between PD and RA varies across RA subtypes. ACPA-positive RA may have a stronger association with PD, potentially due to shared pathogenic mechanisms involving citrullination processes induced by periodontal pathogens like P. gingivalis. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) Furthermore, the exact role of ACPA antibodies in mediating this relationship is still under investigation. ACPA positivity often precedes clinical arthritis by several years, indicating that the immune response to citrullinated proteins may be an early event in RA pathogenesis, potentially triggered or exacerbated by oral bacteria. (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) Recent research has further explored the connection between oral health and systemic disease by examining episodes of oral bacteraemia in RA patients. These episodes, which involve the translocation of oral bacteria into the bloodstream, appear to trigger systemic immune responses, including the production of ACPA antibodies. These findings suggest that oral bacteria, particularly those that undergo citrullination in the oral cavity, may contribute to systemic inflammation and disease relapse in RA patients. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) Although growing evidence implicates oral pathogens, citrullination processes, and systemic immune activation in this association, the precise mechanisms linking periodontitis to RA development remain unclear. Consistent with these uncertainties, the ESPERA randomized controlled trial demonstrated that although periodontal treatment significantly improved periodontal health in RA patients, it did not translate into measurable changes in RA disease activity or overall quality of life. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) Taken together, these findings highlight a complex, potentially bidirectional relationship between periodontitis and rheumatoid arthritis, in which oral inflammation may contribute to RA onset and progression, yet clinical interventions targeting periodontal disease alone may not be sufficient to modify systemic disease activity.\u003c/p\u003e \u003cp\u003eGiven the established role of systemic inflammation in the pathogenesis of RA and its association with periodontal disease, attention has turned to molecular mediators such as CHI3L1, which may link oral and systemic inflammatory processes. In the context of oral inflammation, CHI3L1 levels have been shown to increase stimulation with tumor necrosis factor alpha (TNF-α) in human oral epithelial cells, specifically in the HSC3 and HSC4 cell lines. Patient samples have confirmed higher CHI3L1 expression in inflamed lesions, indicating a key role for CHI3L1 in oral inflammation and the development of conditions like periodontitis. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) This aligns with our study's findings suggesting a potential link between CHI3L1 and periodontal disease, especially in patients with systemic inflammatory conditions.\u003c/p\u003e \u003cp\u003eIn contrast to the findings reported by Sanfilippo et al. (2019), (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) our study observed higher serum CHI3L1 levels in male participants. One possible explanation for this discrepancy is that circulating CHI3L1 levels may not directly reflect its expression in the brain, highlighting tissue-specific differences in CHI3L1 regulation. Additionally, genetic variability in the CHI3L1 gene may contribute to differences in serum CHI3L1 levels. Nielsen et al. (2011) identified a significant association between the g.-131 (C\u0026thinsp;\u0026gt;\u0026thinsp;G) polymorphism (rs4950928) in the CHI3L1 promoter region and serum YKL-40 concentrations in both rheumatoid arthritis patients and healthy controls; however, they did not observe sex-related differences, in contrast to our findings. This suggests that additional, yet unidentified factors may contribute to the higher serum CHI3L1 levels in males in our cohort. (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn summary, periodontitis and rheumatoid arthritis appear to share a complex, bidirectional relationship. The evidence suggests that oral bacteria, such as P. gingivalis, contribute to the onset and progression of RA through mechanisms such as citrullination, which leads to the formation of ACPA antibodies. In turn, RA patients are at increased risk for developing periodontal disease, which may exacerbate systemic inflammation. The findings underscore the importance of monitoring oral health in patients with autoimmune diseases, as improving periodontal status may help mitigate systemic inflammation and potentially improve disease outcomes. Given the role of CHI3L1 in both inflammation and tissue remodelling, further research into its association with oral health could provide valuable insights into the mechanisms linking periodontitis and systemic inflammatory conditions like RA. Early intervention and treatment of periodontitis in RA patients may therefore offer therapeutic potential for reducing disease activity and improving quality of life.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings underscore a potential connection between oral health and cartilage degradation in patients with AIRD or with osteoarthritis. While no significant differences in CHI3L1 levels were found between AIRD patients and controls, higher plaque index (PI) scores were associated with significantly increased CHI3L1 levels. This observation supports the hypothesis that oral hygiene may influence systemic inflammatory processes, leading to cartilage damage.\u003c/p\u003e \u003cp\u003eFrom a clinical perspective, these findings emphasize the importance of preventing and managing periodontitis as a potential strategy for mitigating systemic inflammation in patients with AIRD. However, further research is warranted to validate these results, particularly through longitudinal and interventional studies. Such research could clarify whether improving oral hygiene and treating periodontitis leads to reductions in systemic inflammatory markers, including CHI3L1, and contribute to better disease management in AIRD patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAIRD – autoimmune inflammatory rheumatic diseases\u003c/p\u003e\n\u003cp\u003eRA – rheumatoid arthritis\u003c/p\u003e\n\u003cp\u003ePsA – psoriatic arthritis\u003c/p\u003e\n\u003cp\u003eAxSpA – axial spondyloarthritis\u003c/p\u003e\n\u003cp\u003eOA – osteoarthritis\u003c/p\u003e\n\u003cp\u003eSLE – systemic lupus erythematosus\u003c/p\u003e\n\u003cp\u003ePD – periodontitis\u003c/p\u003e\n\u003cp\u003eACPAs – anti-citrullinated protein antibodies\u003c/p\u003e\n\u003cp\u003eDMARDs – disease-modifying antirheumatic drugs\u003c/p\u003e\n\u003cp\u003eCHI3L1 – chitinase 3-like 1\u003c/p\u003e\n\u003cp\u003eVAS – Visual Analogue Scale\u003c/p\u003e\n\u003cp\u003eRF – rheumatoid factor\u003c/p\u003e\n\u003cp\u003eanti-CCP – anti-cyclic citrullinated peptide antibodies\u003c/p\u003e\n\u003cp\u003eanti-MCV – anti-mutated citrullinated vimentin antibodies\u003c/p\u003e\n\u003cp\u003eCRP – C-reactive protein\u003c/p\u003e\n\u003cp\u003eESR – erythrocyte sedimentation rate\u003c/p\u003e\n\u003cp\u003eCPITN – Community Periodontal Index of Treatment Needs\u003c/p\u003e\n\u003cp\u003eBOP – Bleeding on Probing\u003c/p\u003e\n\u003cp\u003ePI – Plaque Index\u003c/p\u003e\n\u003cp\u003eGI – Gingival Index\u003c/p\u003e\n\u003cp\u003eCAL – Clinical Attachment Loss\u003c/p\u003e\n\u003cp\u003eCEJ – cement–enamel junction\u003c/p\u003e\n\u003cp\u003eOPG – orthopantomogram\u003c/p\u003e\n\u003cp\u003eBW – bitewing radiograph\u003c/p\u003e\n\u003cp\u003eELISA – enzyme-linked immunosorbent assay\u003c/p\u003e\n\u003cp\u003eSD – standard deviation\u003c/p\u003e\n\u003cp\u003eanti-TNF – anti–tumor necrosis factor alpha\u003c/p\u003e\n\u003cp\u003eVAS – Visual Analogue Scale\u003c/p\u003e\n\u003cp\u003eRF IgG – rheumatoid factor immunoglobulin G\u003c/p\u003e\n\u003cp\u003eRF IgA – rheumatoid factor immunoglobulin A\u003c/p\u003e\n\u003cp\u003eRF IgM – rheumatoid factor immunoglobulin M\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of St. Anne’s University Hospital in Brno (Reference Number: 64V/2022). The approval was granted on 12 October 2022 following review of all required study documents, including the study protocol (V2_300922), patient information sheet, and informed consent form (version_2022_09_30). All participants were informed about the purpose and procedures of the study and provided written informed consent prior to enrolment. All procedures were conducted in accordance with the Declaration of Helsinki and relevant national guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll participants provided written informed consent allowing anonymized data to be used for scientific publication. No identifying information is included in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed during the current study are available from the corresponding author on reasonable request. Due to ethical and privacy restrictions, individual-level clinical data cannot be made publicly available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by St. Anne's University Hospital in Brno Support for Internal Pilot Research Projects (grant no. FNDN_IP23IPV02EXA_PN and grant no. FNDN_IP24IPV02EXA_PN) and by project MUNI/A/1768/2024. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdam Lukac\u003cstrong\u003e – \u003c/strong\u003eprincipal investigator; corresponding author, conceptualisation, study design, patient recruitment, data collection, data interpretation, and manuscript drafting. 2nd Department of Internal Medicine, Faculty of Medicine of Masaryk University and St. Anne´s University Hospital in Brno, https://orcid.org/0000-0002-2946-1463\u003c/p\u003e\n\u003cp\u003eEva Buchalova\u003cstrong\u003e – \u003c/strong\u003esub-investigator; clinical examinations, periodontal assessments, data collection. Clinic of Stomatology, Faculty of Medicine, Masaryk University\u003c/p\u003e\n\u003cp\u003eLucie Buresova, St. Anne’s University Hospital in Brno, Center for International Clinical Research, Faculty of Medicine of Masaryk University, https://orcid.org/0000-0003-4193-0194\u003c/p\u003e\n\u003cp\u003eJana Sistkova, Department of Pathophysiology Faculty of Medicine, Masaryk University, Brno, https://orcid.org/0000-0001-6378-1631\u003c/p\u003e\n\u003cp\u003ePetr Němec, 2nd Department of Internal Medicine, Faculty of Medicine of Masaryk University and St. Anne´s University Hospital in Brno, https://orcid.org/0000-0003-2287-7615\u003c/p\u003e\n\u003cp\u003eMonika Pavkova Goldbergova, Department of Pathophysiology Faculty of Medicine, Masaryk University, Brno, https://orcid.org/0000-0002-3471-8702\u003c/p\u003e\n\u003cp\u003eLydie Izakovicova Holla) – senior author; critical revision of the manuscript for important intellectual content; Clinic of Stomatology, Faculty of Medicine, Masaryk University; ORCID: https://orcid.org/0000-0002-7610-8929\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by St. Anne's University Hospital in Brno Support for Internal Pilot Research Projects (grant no. FNDN_IP23IPV02EXA_PN and grant no. FNDN_IP24IPV02EXA_PN) and by project MUNI/A/1768/2024. \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eden Hollander NK, Verstappen M, Huizinga TW, van der Helm-van Mil A. Management of contemporary early undifferentiated arthritis: data on EULAR\u0026apos;s recommendation on the risk of persistent disease. Ann Rheum Dis. 2022;81(5):740\u0026ndash;1. http://dx.doi.org/10.1136/annrheumdis-2021-221821\u003c/li\u003e\n \u003cli\u003eSlots J. Periodontitis: Facts, fallacies, and the future. Periodontol 2000. 2017;75(1):7\u0026ndash;23. http://dx.doi.org/10.1111/prd.12221\u003c/li\u003e\n \u003cli\u003eDe Pablo P, Dietrich T, McAlindon TE. Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. J Rheumatol. 2008;35(1):70\u0026ndash;6. (no DOI available)\u003c/li\u003e\n \u003cli\u003eEke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ, Beck J, et al. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 2012;91(10):914\u0026ndash;20. http://dx.doi.org/10.1177/0022034512457373\u003c/li\u003e\n \u003cli\u003eEriksson K, Fei G, Lundmark A, et al. Periodontal health and oral microbiota in patients with rheumatoid arthritis. J Clin Med. 2019;8(5):630. http://dx.doi.org/10.3390/jcm8050630\u003c/li\u003e\n \u003cli\u003eSilva DS, de Vries C, Rovisco J, Serra S, Kaminska M, Mydel P, et al. The impact of periodontitis and periodontal treatment on rheumatoid arthritis outcomes: an exploratory clinical trial. Rheumatology (Oxford). 2025;64(4):1679\u0026ndash;88. http://dx.doi.org/10.1093/rheumatology/keae358\u003c/li\u003e\n \u003cli\u003e\u0026Auml;yr\u0026auml;v\u0026auml;inen L, Leirisalo-Repo M, Kuuliala A, Ahola K, Koivuniemi R, Meurman JH, Heikkinen AM. Periodontitis in early and chronic rheumatoid arthritis: a prospective follow-up study in Finnish population. BMJ Open. 2017;7(1):e011916. http://dx.doi.org/10.1136/bmjopen-2016-011916\u003c/li\u003e\n \u003cli\u003eHussain SB, Leira Y, Zehra SA, Botelho J, Machado V, Ciurtin C, et al. Periodontitis and systemic lupus erythematosus: A systematic review and meta-analysis. J Periodontal Res. 2022;57(1):1\u0026ndash;10. http://dx.doi.org/10.1111/jre.12936\u003c/li\u003e\n \u003cli\u003eConrozier, T., Carlier, M. C., Mathieu, P., Colson, F., Debard, A. L., Richard, S., Favret, H., Bienvenu, J., \u0026amp; Vignon, E. (2000). Serum levels of YKL-40 and C reactive protein in patients with hip osteoarthritis and healthy subjects: a cross sectional study. Annals of the rheumatic diseases, 59(10), 828\u0026ndash;831. https://doi.org/10.1136/ard.59.10.828\u003c/li\u003e\n \u003cli\u003eMayer Y, Elimelech R, Balbir-Gurman A, Braun-Moscovici Y, Machtei EE. Periodontal condition of patients with autoimmune diseases and the effect of anti-tumor necrosis factor-\u0026alpha; therapy. J Periodontol. 2013;84(2):136\u0026ndash;42. http://dx.doi.org/10.1902/jop.2012.120009\u003c/li\u003e\n \u003cli\u003ePischon N, Pischon T, Kr\u0026ouml;ger J, G\u0026uuml;lmez E, Kleber BM, Bernimoulin JP, et al. Association among rheumatoid arthritis, oral hygiene, and periodontitis. J Periodontol. 2008;79(6):979\u0026ndash;86. http://dx.doi.org/10.1902/jop.2008.070501\u003c/li\u003e\n \u003cli\u003eGomez-Banuelos E, Mukherjee A, Darrah E, Andrade F. Rheumatoid arthritis-associated mechanisms of Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. J Clin Med. 2019;8(9):1309. http://dx.doi.org/10.3390/jcm8091309\u003c/li\u003e\n \u003cli\u003eQiao Y, Wang Z, Li Y, Han Y, Zhou Y, Cao X. Rheumatoid arthritis risk in periodontitis patients: A systematic review and meta-analysis. Joint Bone Spine. 2020;87(6):556\u0026ndash;64. http://dx.doi.org/10.1016/j.jbspin.2020.04.024\u003c/li\u003e\n \u003cli\u003eFang, H., Lin, J., Qiu, Y., Cheng, Z., \u0026amp; Chen, W. (2025). Epidemiology and pathogenesis of the link between rheumatoid arthritis and periodontitis. Journal of Zhejiang University. Science. B, 26(5), 448\u0026ndash;460. https://doi.org/10.1631/jzus.B2300519\u003c/li\u003e\n \u003cli\u003eKhatri S, Hansen J, Astakhova K. Antibodies to synthetic citrullinated peptide epitope correlate with disease activity and flares in rheumatoid arthritis. PLoS One. 2020;15(4):e0232010. http://dx.doi.org/10.1371/journal.pone.0232010\u003c/li\u003e\n \u003cli\u003eBrewer RC, Lanz TV, Hale CR, Sepich-Poore GD, Martino C, Swafford AD, Carroll TS, et al. Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis. Sci Transl Med. 2023;15(684):eabq8476. http://dx.doi.org/10.1126/scitranslmed.abq8476\u003c/li\u003e\n \u003cli\u003eMonsarrat P, De Grado GF, Constantin A, et al. The effect of periodontal treatment on patients with rheumatoid arthritis: The ESPERA randomised controlled trial. Joint Bone Spine. 2019;86(4):439\u0026ndash;40. http://dx.doi.org/10.1016/j.jbspin.2019.02.006\u003c/li\u003e\n \u003cli\u003eTeratani Y. Chitinase 3-Like-1 Expression Is Upregulated Under Inflammatory Conditions in Human Oral Epithelial Cells. Kurume Med J. 2023;68(3\u0026ndash;4):221\u0026ndash;8. http://dx.doi.org/10.2739/kurumemedj.MS6834014\u003c/li\u003e\n \u003cli\u003eSanfilippo, C., Castrogiovanni, P., Imbesi, R., Kazakowa, M., Musumeci, G., Blennow, K., Zetterberg, H., \u0026amp; Di Rosa, M. (2019). Sex difference in CHI3L1 expression levels in human brain aging and in Alzheimer\u0026apos;s disease. Brain research, 1720, 146305. https://doi.org/10.1016/j.brainres.2019.146305\u003c/li\u003e\n \u003cli\u003eNielsen KR, Steffensen R, Boegsted M, Baech J, Lundbye-Christensen S, Hetland ML, et al. Promoter polymorphisms in the chitinase 3-like 1 gene influence the serum concentration of YKL-40 in Danish patients with rheumatoid arthritis and in healthy subjects. Arthritis Res Ther. 2011;13(3):R109. http://dx.doi.org/10.1186/ar3391\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Rheumatoid arthritis, Periodontitis, Oral microbiota, Citrullination, Systemic inflammation","lastPublishedDoi":"10.21203/rs.3.rs-8305752/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8305752/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eAutoimmune rheumatic diseases (AIRD), such as rheumatoid arthritis (RA), often co-exist with periodontitis (PD). Both diseases share inflammatory pathways and common risk factors, suggesting a potential interplay. This study evaluates the association between periodontal health and Chitinase 3-Like-1 (CHI3L1), a serological marker of cartilage damage, in patients with or without AIRD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn a cross-sectional design, 36 participants (AIRD patients and controls) underwent rheumatological and periodontal assessments. Clinical data included inflammatory markers, CHI3L1 levels, and detailed periodontal health metrics. Statistical analyses were performed to examine differences between groups and correlations between periodontal indices and CHI3L1 concentrations, adjusting for age and sex.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWhile no significant differences in CHI3L1 levels were found between AIRD and control groups, male participants and individuals with higher Plaque Index (PI) scores exhibited significantly elevated CHI3L1 concentrations. Linear regression indicated PI as a significant predictor of CHI3L1 levels, with a 62% increase per PI unit. The AIRD group showed higher inflammatory marker levels overall.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCHI3L1 levels correlated with the severity of periodontal disease, with higher concentrations observed in individuals with poorer oral health. These findings indicate that CHI3L1 is associated with periodontitis independently of the presence of AIRD in patients presenting with joint pain. Further longitudinal studies are needed to clarify causal relationships and to determine whether improving periodontal health can reduce systemic inflammation in patients with AIRD.\u003c/p\u003e","manuscriptTitle":"Periodontal Health and Chitinase 3-Like-1 Levels in Autoimmune Rheumatic Diseases and Osteoarthritis ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-13 12:22:59","doi":"10.21203/rs.3.rs-8305752/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-31T08:00:47+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"336741156437374468888677353537129639747","date":"2026-03-30T04:08:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"270597490809799139789991351520083843776","date":"2026-03-28T07:56:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-27T23:45:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225230075344008601014562529979554671025","date":"2026-03-17T21:00:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-01T19:12:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"339412949892318540303799329139280339629","date":"2026-02-10T05:42:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-09T19:24:49+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-05T10:02:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-09T02:40:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-09T02:39:41+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Oral Health","date":"2025-12-08T09:04:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-oral-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ohea","sideBox":"Learn more about [BMC Oral Health](http://bmcoralhealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ohea/default.aspx","title":"BMC Oral Health","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e6e1230e-b95f-4bd0-85bd-691c74bef25f","owner":[],"postedDate":"February 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-17T15:38:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-13 12:22:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8305752","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8305752","identity":"rs-8305752","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}