Progranulin in the Differentiation of Septic and Inflammatory Arthritis

Progranulin in the Differentiation of Septic and Inflammatory Arthritis | 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 Progranulin in the Differentiation of Septic and Inflammatory Arthritis Toktamış Savaş, İpek Koçer, Fatih Albayrak, Nurcihan Yavuz Savaş, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9102472/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 9 You are reading this latest preprint version Abstract Background: Septic arthritis (SA) is a rapidly progressive joint disease that can lead to cartilage damage if not promptly treated. A prompt and accurate distinction between SA and inflammatory arthritis (IA) is essential to establish an optimal treatment plan. Progranulin (PRGN), an anti-inflammatory glycoprotein involved in various autoimmune diseases, has scarcely been studied as a diagnostic biomarker of infectious arthritis. Its precise role in this context remains to be elucidated. This study aimed to evaluate the diagnostic utility of synovial fluid PRGN (SF-PRGN) in distinguishing SA from IA and osteoarthritis (OA). Methods: This single-center, cross-sectional study included 59 patients who underwent synovial fluid aspiration and were categorized into three groups: SA (n = 23), IA (n = 18), and OA (n = 18). SA was diagnosed based on positive synovial fluid culture or fulfillment of clinical criteria suggestive of infection. SF-PRGN levels were measured using ELISA, and synovial fluid C-reactive protein (SF-CRP) levels were determined using an immunoturbidimetric assay. Results: Mean SF-PRGN levels were higher in the SA (339.77 ± 142.16 ng/mL) and IA (300.52 ± 159.60 ng/mL) groups compared to the OA group (133.44 ± 41.77 ng/mL), indicating a statistically significant difference between inflammatory and non-inflammatory groups (p < 0.05). However, the SF-PRGN did not significantly differentiate between SA and IA (p = 0.803). In contrast, SF-CRP levels were markedly elevated in SA (61.91 ± 46.84 mg/L) and demonstrated a strong discriminatory power between SA and IA (p < 0.001; AUC: 0.795, p < 0.0001). Conclusion: Although SF-PRGN was elevated in inflammatory arthritis, it lacked specificity for SA. SF-CRP showed superior diagnostic accuracy in differentiating SA from IA. These findings underscore the need for further research on reliable biomarkers for SA in larger patient cohorts. Septic Arthritis Inflammatory Arthritis Progranulin C-Reactive Protein Synovial Fluid Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Septic arthritis (SA) is an acute joint condition that can lead to rapid joint destruction if not promptly diagnosed and treated ( 1 , 2 ). A delayed diagnosis often results in significant articular damage. However, the clinical presentation of SA may overlap with other types of arthritis, and diagnosis largely relies on culture-based methods, which are time-consuming and may delay definitive management ( 1 ). In rheumatology practice, it is crucial to differentiate whether a newly emerging arthritis is attributable to SA or inflammatory arthritis (IA), particularly in patients presenting with symptoms suggestive of diseases such as rheumatoid arthritis (RA) or psoriatic arthritis. Progranulin (PRGN) is an 80-kDa glycoprotein originally identified as a growth factor in cancer cells and fibroblasts, with established anti-inflammatory and chondroprotective properties ( 3 ). Its levels have been shown to increase under inflammatory conditions and correlate with disease activity in RA and systemic lupus erythematosus (SLE) ( 4 – 9 ). Conventional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are widely used in clinical practice; however, they often lack specificity in distinguishing SA from non-infectious arthritis, as they may be elevated in both infection and flare-ups of inflammatory diseases. Furthermore, the limitations of culture-based diagnosis, —including positive yields in only 40–54% of SA cases, delayed results (24–72 h), and low leukocyte counts in the early stages of infection ( 1 , 10 – 13 )—underscore the ongoing need for novel biomarkers. Despite the theoretical potential of PRGN in distinguishing infectious from inflammatory processes, its diagnostic performance in differentiating SA from IA has not been thoroughly evaluated. This study aimed to address this gap in the literature by investigating the potential of PRGN as a clinical biomarker for the differential diagnosis of SA. MATERIALS AND METHODS This cross-sectional study was conducted in a single-center setting involving both orthopedic and rheumatology outpatient clinics. Synovial fluid (SF) samples were obtained from patients presenting with arthritis of the knee, as clinically indicated by specialists in orthopedics and rheumatology. Patients who presented with knee pain and demonstrated findings such as pain during joint movement, weight-bearing difficulty, local swelling, warmth, and tenderness on physical examination and from whom synovial fluid could be aspirated were considered eligible for inclusion. Among these, patients fulfilling Kocher's criteria (fever, inability to bear weight, leukocytosis, elevated ESR/CRP) were classified into the septic arthritis (SA) group, those with rheumatologic causes of arthritis were assigned to the inflammatory arthritis (IA) group, and patients with clinical and radiographic findings consistent with primary osteoarthritis were enrolled in the control group (OA). Positive synovial fluid culture was used as the reference standard for SA diagnosis. Patients with negative cultures but who showed either positive Gram staining or SF leukocyte counts > 50,000 cells/mm³ and clinical findings suggestive of SA were included in the SA group. The IA group included patients diagnosed with RA, PsA, and AS according to the classification criteria of the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR). Aspirations in both patients with SA and IA were performed during active arthritis flares. In the OA group, aspiration was performed for therapeutic and diagnostic purposes because of symptomatic joint effusion. As synovial sampling from healthy individuals was not ethically permissible, patients with OA served as the non-inflammatory control group. Patients who were receiving immunosuppressive or antibiotic therapy during the arthritis flare or had traumatic osteoarthritis, previous arthroplasty, or malignancy were excluded. A total of 59 patients aged 18–83 years who met the inclusion criteria were evaluated and assigned to three groups: SA (n = 23), IA (n = 18), and OA (n = 18). Joint aspiration was performed based on patient positioning: in the supine position, aspiration was performed from the patellofemoral joint, and in the seated position, from the femorotibial compartment. Prior to aspiration, the injection site was sterilized with 10% povidone-iodine and allowed to sit for 2 min. The procedure was performed using 18G or 21G spinal needles. SF samples were first processed in the microbiology laboratory of the Center for Culture and Gram staining. Each sample was inoculated into BacT/ALERT FA Plus aerobic bottles (bioMérieux, France) and incubated using at BD BACTEC Fx automated system (Becton, Dickinson and Company, USA). Positive signals were subcultured on 5% sheep blood agar (RTA, Turkey) and MacConkey agar (RTA, Turkey), and evaluated after 18–24 h of incubation at 37°C. Identification and susceptibility testing of microorganisms were performed using conventional methods and at BD Phoenix 100 automated system (Becton, Dickinson and Company, USA). The SF samples remaining after microbiological evaluation were stored at -80°C. On the day of analysis, the samples were thawed at room temperature in a single-step process to minimize contamination. CRP levels were measured using an immunoturbidimetric assay with an Alinity c analyzer (Abbott Laboratories, USA), and the same samples were used for PRGN measurement by ELISA. PRGN concentrations were determined in accordance with the manufacturer’s instructions using an ELISA kit (BT LAB, Shanghai Korain Biotech Co., Ltd., China) and are reported in ng/mL. Statistical Analysis The normality of the numerical variables was assessed using the Kolmogorov–Smirnov test. As parametric assumptions were not met, comparisons between groups were performed using the Kruskal–Wallis test, and pairwise comparisons were conducted using the Mann–Whitney U test. Categorical variables were analyzed using the chi-square test. Receiver Operating Characteristic (ROC) curve analysis was used to assess the discriminatory ability of the variables. Diagnostic accuracy was evaluated using ROC curves, and optimal cut-off values were determined using the Youden Index. The area under the curve (AUC) values were reported with 95% confidence intervals (CI). ROC analysis was conducted separately for SF-CRP and SF-PRGN to assess their performance in distinguishing SA from IA and OA, respectively. The resulting AUC values were used to determine the diagnostic accuracy of each biomarker. Diagnostic performance parameters including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Logistic regression analysis was used for the multivariate analysis. Statistical significance was set at P < 0.05. All statistical analyses were performed using IBM SPSS Statistics version 23 (IBM Corp., Armonk, NY, USA). RESULTS A total of 59 patients who met the inclusion criteria were enrolled and categorized into three groups: SA (n = 23), IA (n = 18), and OA (n = 18). The mean ages were 50.7 ± 18.5 years in the SA group, 46.6 ± 11.4 years in the IA group, and 52.8 ± 18.2 years in the OA group. There were no statistically significant differences between the groups in terms of age or sex (P > 0.05). Demographic and clinical characteristics of the study groups are shown in Table 1 . Table 1 Demographic, Clinical, and Laboratory Characteristics of Patients with Septic Arthritis, Inflammatory Arthritis, and Osteoarthritis. Pairwise Comparisons of SF-CRP and SF-Prgn Levels in Different Study Groups Variables Groups p-value Culture (-) SA (n = 13) Mean ± SD Median (Min-Max) Culture (+) SA (n = 10) Mean ± SD Median (Min-Max) IA (n = 18) Mean ± SD Median (Min-Max) OA (n = 18) Mean ± SD Median (Min-Max) Sex Male 2 5 8 7 0.287 * Female 11 5 10 11 Age (years) 53.54 ± 17.75 49 (27–81) 47 ± 19.79 44.5 (21–75) 46.56 ± 11.41 43 (31–78) 52.83 ± 18.24 51.5 (14–83) 0.542 † SF-CRP (mg/L) 55.41 ± 34.72 64.2 (0-108.9) 70.37 ± 60.13 69.75 (0-188.1) 18.97 ± 18.17 18.25 (0-60.6) 1.53 ± 2.31 0.5 (0-8.2) < 0.001 † SF-Prgn (ng/ml) 330.37 ± 156.2 294.07 (165.32-726.18) 351.99 ± 128.76 333.59 (168.75-523.79) 300.52 ± 159.6 296.39 (92.43-793.54) 133.44 ± 41.77 130.02 (52.79-211.57) < 0.001 † *: The sex variable was analyzed using the Chi-square test. †: Continuous variables were analyzed using the Kruskal–Wallis test. Synovial fluid culture was positive in 10 of 23 patients (43.5%) in the SA group. The most frequently isolated microorganisms were Staphylococcus aureus (26.1%), Streptococcus spp. (4.3%), Staphylococcus epidermidis (4.3%), Klebsiella pneumoniae (4.3%), and Group A beta-hemolytic Streptococcus (4.3%). The remaining 13 patients (56.5%) in the SA group showed culture-negative results, whereas all synovial fluid samples from the IA and OA groups were sterile. Significant differences were observed among the groups in terms of the SF-PRGN and SF-CRP levels. The SA group was further subdivided into culture-positive (SA[+]) and culture-negative (SA[–]). The mean SF-PRGN levels were 330.37 ± 156.2 ng/mL in the SA(–) subgroup, 351.99 ± 128.76 ng/mL in the SA(+) subgroup, 300.52 ± 159.60 ng/mL in the IA group, and 133.44 ± 41.77 ng/mL in the OA group. The corresponding SF-CRP levels were 61.91 ± 46.84 mg/L in SA, 18.97 ± 18.17 mg/L in IA, and 1.64 ± 2.25 mg/L in OA. The Kruskal–Wallis test was used for group comparisons of continuous variables, followed by post hoc analyses for variables showing significant differences. The results of the post hoc comparisons are presented in Table 2 , and the graphical distribution of SF-PRGN and SF-CRP levels across all groups is shown in Fig. 1 and Fig. 2 . SF-CRP levels were significantly higher in the SA group than in both IA and OA groups (p < 0.001 for both). No statistically significant difference was observed in the SF-PRGN levels between the SA and IA groups (p = 0.803); however, the levels in the OA group were significantly lower than those in the SA and IA groups (p < 0.001 for both). Subgroup analysis revealed no significant differences in SF-CRP and SF-PRGN levels between the culture-positive and culture-negative SA patients (p = 0.983 and p = 0.999, respectively). Table 2 Pairwise comparisons of SF-CRP and SF-Prgn levels among study groups using Tamhane’s T2 post hoc test Groups Compared SF-CRP (p) SF-Prgn (p) SA vs IA < 0.001 ** .803 IA vs OA .004 ** .002 ** SA vs OA < 0.001 ** < 0.001 ** SA(-) vs SA(+) .983 .999 SA(-) vs. IA .018 ** .996 SA(-) vs OA < 0.001 ** .003 ** SA(+) vs IA .141 .933 SA(+) vs OA .032 ** .002 ** **: p < 0.05 The diagnostic performance analyses of SF-CRP and SF-PRGN are presented in Table 3 , Fig. 3 and Fig. 4 . The diagnostic accuracy of SF-CRP for differentiating SA from IA was high, with an AUC of 0.795 (95% CI: 0.640–0.905, p 50.4 mg/L, with a sensitivity of 60.87% and specificity of 94.44%. For SF-PRGN, ROC analysis yielded an AUC of 0.585 for distinguishing SA from IA, which was not statistically significant (p = 0.3603). Using a cutoff value of > 458.46 ng/mL, the sensitivity was 30.43%, and the specificity was 94.44%. For differentiating SA from OA, the AUC values were 0.923 (95% CI: 0.795–0.983, p < 0.0001) and 0.971 (95% CI: 0.864–0.999, p < 0.0001) for the SF-PRGN. Table 3 Diagnostic Performance of SF-CRP and SF-Prgn in Differentiating SA, IA, and OA: ROC Curve Analysis. Test AUC (95%CI) Cut-off Value Sensitivity (%) Specificity (%) SF-CRP (SA vs IA) 0.795 (0.640–0.905) > 50.4 mg/L 60.87 94.44 SF-Prgn (SA vs IA) 0.585 (0.420–0.760) > 458.46 ng/mL 30.43 94.44 SF-CRP (SA vs OA) 0.923 (0.795–0.983) > 8.2 mg/L 86.96 100.00 SF-Prgn (SA vs OA) 0.971 (0.864–0.999) > 171.07 ng/mL 91.30 88.89 SF-CRP (IA vs OA) 0.802 (0.636–0.916) > 8.2 mg/L 66.67 100.00 SF-Prgn (IA vs OA) 0.880 (0.728–0.964) > 171.07 ng/mL 83.33 88.89 DISCUSSION This study compared the diagnostic performance of synovial fluid CRP and PRGN levels in patients with SA, IA, and OA, focusing on their ability to distinguish between SA and IA. Our findings revealed that while SF-PRGN levels were significantly elevated in both the SA and IA groups compared to OA, they did not differ significantly between SA and IA. In contrast, SF-CRP levels demonstrated a high diagnostic accuracy in differentiating SA from IA, with significantly higher values observed in the SA group. PRGN is a glycoprotein with anti-inflammatory and chondroprotective properties, and its expression has been shown to increase in various inflammatory arthropathies, typically linked to heightened immune activation and TNF-α mediated pathways ( 4 – 9 , 14 ). Based on this mechanism, a significant difference in SF-PRGN levels between SA and IA patients was expected. Although SF-PRGN levels were higher in SA patients than in IA patients, the difference was not statistically significant. Several factors might explain this outcome. First, chronic inflammatory arthritis such as RA and psoriatic arthritis, is characterized by persistent synovial proliferation and elevated inflammatory burden. These conditions may result in the activation or suppression of various cytokines, some of which may modulate PRGN expression via distinct mechanisms. In a systematic review comparing OA and IA, Wei et al. reported increased PRGN expression in both diseases, albeit at differing levels. This variation is attributed to the divergent cytokine pathways involved in each disease ( 14 ). Second, although none of the patients with IA were under active immunosuppressive treatment during sample collection, some may have previously received such therapies. Given the long half-life and lasting biological effects of these agents, their residual influence on synovial cytokine responses and PRGN levels is plausible. Importantly, current evidence regarding the role of PRGN in septic arthritis remains limited. While several studies have evaluated PRGN in the context of IA and OA ( 4 , 5 , 9 ), to our knowledge, this is among the first studies to assess SF-PRGN levels specifically in patients with SA, providing a novel contribution to the literature. These findings may serve as a foundation for future studies of PRGN as a potential biomarker. In our study, the proportion of culture-negative SA cases (56.5%) was consistent with that in previous reports; however, this high rate poses a limitation in diagnostic accuracy ( 1 , 10 – 13 , 15 ). The elevated SF-PRGN levels observed in both culture-positive and culture-negative SA patients suggest that PRGN may be upregulated by the inflammatory cytokine response triggered by the infectious process of SA rather than directly by bacterial proliferation. This observation supports the hypothesis that PRGN reflects the overall inflammatory response specific to SA independent of culture positivity. Although various studies have investigated SF-CRP, few have assessed its diagnostic value in distinguishing SA, IA, and OA simultaneously. Zamani et al. found significantly higher SF-CRP levels in patients with IA than in OA ( 16 ). Using a methodology similar to that of our study, Streit et al. reported the highest SF-CRP levels in SA, followed by IA and OA, which is consistent with our findings ( 17 ). Rowe et al. also demonstrated elevated SF-CRP levels in patients with IA compared to those with OA ( 18 ). These findings collectively support the utility of SF-CRP as a reliable diagnostic marker for differentiating SA from IA and OA. The significant increase in CRP levels in SA may reflect its correlation with inflammation severity. On the other hand, SF-PRGN successfully distinguished inflammatory (SA and IA) from non-inflammatory (OA) conditions but showed lower diagnostic performance than CRP in separating SA from IA. This may indicate that CRP responds more specifically to infection-induced inflammation, whereas PRGN may increase in response to both infectious and non-infectious inflammatory stimuli. This study hads several limitations. First, the relatively small sample size may have limited the statistical power and generalizability of the findings. Second, the assessment was restricted to only two biomarkers—CRP and PRGN, which may not fully capture the complexity of the inflammatory process. In particular, serial sampling of synovial fluid in patients with SA could provide insights into the dynamic changes in biomarker levels throughout the disease course. In conclusion, our results suggest that SF-CRP demonstrates high diagnostic accuracy in distinguishing SA from IA and OA, and may serve as a reliable marker of infection-associated inflammation. Although SF-PRGN levels were elevated in SA and demonstrated a high AUC (0.971) in distinguishing SA from OA, its performance in differentiating SA from IA was limited by its low sensitivity (30.43%) and lack of statistical significance. These findings suggest that PRGN may reflect the overall inflammatory activity rather than act as a specific marker for infection. Future studies with larger cohorts and prospective designs are warranted to elucidate the role of PRGN in differentiating SA from IA, particularly with careful control of clinical variables such as disease activity, treatment history, and timing of sample collection. Declarations Clinical Trial Registration: Clinical trial number: not applicable. Human Ethics and Consent to Participate: The study protocol was approved by the Scientific Research Ethics Committee of SANKO University (Approval Number: 2024/6). Written informed consent was obtained from all participants and the study was conducted in accordance with the Declaration of Helsinki. Ethics Statement: All participants provided written informed consent before inclusion in the study. Competing Interests: The authors declare that they have no relevant financial or non-financial interests to disclose. This has also been indicated in the ICMJE Conflict of Interest Form. Informed Consent: Informed consent was obtained from all individual participants included in the study Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors Author Contribution T.S. conceptualized and designed the study, coordinated patient recruitment, performed the statistical analyses, and drafted the initial manuscript.İ.K. performed the microbiological analyses, including synovial fluid culture and laboratory processing, and contributed to data interpretation.F.A. contributed to the clinical evaluation of patients with inflammatory arthritis and participated in data collection.N.Y.S. contributed to the radiological evaluation and interpretation of imaging findings.Ç.K. assisted in patient recruitment, joint aspiration procedures, and clinical data collection.B.K. supervised the study, contributed to the clinical interpretation of the results, and critically revised the manuscript for important intellectual content.All authors reviewed and approved the final version of the manuscript. Data Availability The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. References Domagała A, Macura B, Piekarz K, Kiecka A. Septic arthritis–symptoms, diagnosis and new therapy. Eur J Clin Microbiol Infect Dis. 2025:1–11. Ross JJ. Septic arthritis of native joints. Infect Disease Clin. 2017;31(2):203–18. He Z, Bateman A. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med. 2003;81(10):600–12. Cerezo LA, Kuklová M, Hulejová H, Vernerová Z, Kaspříková N, Veigl D, et al. Progranulin Is Associated with Disease Activity in Patients with Rheumatoid Arthritis. Mediators Inflamm. 2015;2015:740357. Chen J, Li S, Shi J, Zhang L, Li J, Chen S, et al. Serum progranulin irrelated with Breg cell levels, but elevated in RA patients, reflecting high disease activity. Rheumatol Int. 2016;36:359–64. Jing C, Zhang X, Song Z, Zheng Y, Yin Y. 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Synovial fluid adenosine deaminase and high-sensitivity C-reactive protein activity in differentiating monoarthritis. Rheumatol Int. 2012;32(1):183–8. Streit G, Alber D, Toussirot E, Wendling D, Toubin MM, Procalcitonin. C-reactive protein, and complement-3a assays in synovial fluid for diagnosing septic arthritis: Preliminary results. Joint Bone Spine. 2008;75(2):238–9. Rowe I, Sheldon J, Riches P, Keat A. Comparative studies of serum and synovial fluid C reactive protein concentrations. Ann Rheum Dis. 1987;46(10):721–6. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 14 May, 2026 Reviews received at journal 01 May, 2026 Reviews received at journal 22 Apr, 2026 Reviewers agreed at journal 15 Apr, 2026 Reviewers agreed at journal 14 Apr, 2026 Reviewers invited by journal 14 Apr, 2026 Editor assigned by journal 16 Mar, 2026 Submission checks completed at journal 16 Mar, 2026 First submitted to journal 12 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-9102472","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":623700636,"identity":"f93a8b1a-3365-44b8-bb24-3e63eeab9b09","order_by":0,"name":"Toktamış 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Albayrak","email":"","orcid":"","institution":"Gaziantep University, Şahinbey Research and Practice Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fatih","middleName":"","lastName":"Albayrak","suffix":""},{"id":623700640,"identity":"4799009e-b9ef-43b2-b62b-5995eb1b6646","order_by":3,"name":"Nurcihan Yavuz Savaş","email":"","orcid":"","institution":"SANKO University, School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Nurcihan","middleName":"Yavuz","lastName":"Savaş","suffix":""},{"id":623700642,"identity":"24b137c2-87f7-4f90-9755-e6c07632770a","order_by":4,"name":"Çağrı Karabulut","email":"","orcid":"","institution":"Pazarcık State Hospital","correspondingAuthor":false,"prefix":"","firstName":"Çağrı","middleName":"","lastName":"Karabulut","suffix":""},{"id":623700650,"identity":"63f76505-adf8-4972-b83b-8ba33adb6f23","order_by":5,"name":"Bünyamin Kısacık","email":"","orcid":"","institution":"SANKO University, School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Bünyamin","middleName":"","lastName":"Kısacık","suffix":""}],"badges":[],"createdAt":"2026-03-12 08:54:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9102472/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9102472/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107500417,"identity":"e9b491a2-8355-42ab-a2f0-0d524428afda","added_by":"auto","created_at":"2026-04-22 05:46:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":185349,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of SF-PRGN levels among SA, IA, and OA groups\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9102472/v1/1dee9f4cd6541c83ec849f26.jpg"},{"id":107705290,"identity":"305e92d6-e32c-48d5-b3a0-bb8f01f36943","added_by":"auto","created_at":"2026-04-24 09:10:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":271976,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of SF-CRP levels among SA, IA, and OA groups\u003c/p\u003e","description":"","filename":"Picture2.png","url":"https://assets-eu.researchsquare.com/files/rs-9102472/v1/6a7fb1ed71b753228584e3ad.png"},{"id":107705948,"identity":"67b36b9d-c313-499e-be4a-585cd81daa9d","added_by":"auto","created_at":"2026-04-24 09:15:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":243961,"visible":true,"origin":"","legend":"\u003cp\u003eROC curves of SF-PRGN levels for distinguishing SA, IA and OA\u003c/p\u003e","description":"","filename":"Picture3.png","url":"https://assets-eu.researchsquare.com/files/rs-9102472/v1/49bf0d0e1f44de8d2301259c.png"},{"id":107500419,"identity":"9a1d9dab-d1be-40d2-a28b-150e3ffa4477","added_by":"auto","created_at":"2026-04-22 05:46:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":79144,"visible":true,"origin":"","legend":"\u003cp\u003eROC curves of SF-PRGN levels for distinguishing SA, IA and OA\u003c/p\u003e","description":"","filename":"Picture4.png","url":"https://assets-eu.researchsquare.com/files/rs-9102472/v1/c16a08616f8f5a31c733060c.png"},{"id":107708986,"identity":"f016c88d-cc85-4635-a9bd-768dafcd9600","added_by":"auto","created_at":"2026-04-24 09:34:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":894572,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9102472/v1/017ab185-ff1e-4e08-8501-3c485a86ef58.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eProgranulin in the Differentiation of Septic and Inflammatory Arthritis\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSeptic arthritis (SA) is an acute joint condition that can lead to rapid joint destruction if not promptly diagnosed and treated (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). A delayed diagnosis often results in significant articular damage. However, the clinical presentation of SA may overlap with other types of arthritis, and diagnosis largely relies on culture-based methods, which are time-consuming and may delay definitive management (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In rheumatology practice, it is crucial to differentiate whether a newly emerging arthritis is attributable to SA or inflammatory arthritis (IA), particularly in patients presenting with symptoms suggestive of diseases such as rheumatoid arthritis (RA) or psoriatic arthritis.\u003c/p\u003e \u003cp\u003eProgranulin (PRGN) is an 80-kDa glycoprotein originally identified as a growth factor in cancer cells and fibroblasts, with established anti-inflammatory and chondroprotective properties (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Its levels have been shown to increase under inflammatory conditions and correlate with disease activity in RA and systemic lupus erythematosus (SLE) (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Conventional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are widely used in clinical practice; however, they often lack specificity in distinguishing SA from non-infectious arthritis, as they may be elevated in both infection and flare-ups of inflammatory diseases.\u003c/p\u003e \u003cp\u003eFurthermore, the limitations of culture-based diagnosis, \u0026mdash;including positive yields in only 40\u0026ndash;54% of SA cases, delayed results (24\u0026ndash;72 h), and low leukocyte counts in the early stages of infection (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u0026mdash;underscore the ongoing need for novel biomarkers. Despite the theoretical potential of PRGN in distinguishing infectious from inflammatory processes, its diagnostic performance in differentiating SA from IA has not been thoroughly evaluated. This study aimed to address this gap in the literature by investigating the potential of PRGN as a clinical biomarker for the differential diagnosis of SA.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eThis cross-sectional study was conducted in a single-center setting involving both orthopedic and rheumatology outpatient clinics. Synovial fluid (SF) samples were obtained from patients presenting with arthritis of the knee, as clinically indicated by specialists in orthopedics and rheumatology.\u003c/p\u003e \u003cp\u003ePatients who presented with knee pain and demonstrated findings such as pain during joint movement, weight-bearing difficulty, local swelling, warmth, and tenderness on physical examination and from whom synovial fluid could be aspirated were considered eligible for inclusion. Among these, patients fulfilling Kocher's criteria (fever, inability to bear weight, leukocytosis, elevated ESR/CRP) were classified into the septic arthritis (SA) group, those with rheumatologic causes of arthritis were assigned to the inflammatory arthritis (IA) group, and patients with clinical and radiographic findings consistent with primary osteoarthritis were enrolled in the control group (OA).\u003c/p\u003e \u003cp\u003ePositive synovial fluid culture was used as the reference standard for SA diagnosis. Patients with negative cultures but who showed either positive Gram staining or SF leukocyte counts\u0026thinsp;\u0026gt;\u0026thinsp;50,000 cells/mm\u0026sup3; and clinical findings suggestive of SA were included in the SA group. The IA group included patients diagnosed with RA, PsA, and AS according to the classification criteria of the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR). Aspirations in both patients with SA and IA were performed during active arthritis flares. In the OA group, aspiration was performed for therapeutic and diagnostic purposes because of symptomatic joint effusion. As synovial sampling from healthy individuals was not ethically permissible, patients with OA served as the non-inflammatory control group.\u003c/p\u003e \u003cp\u003ePatients who were receiving immunosuppressive or antibiotic therapy during the arthritis flare or had traumatic osteoarthritis, previous arthroplasty, or malignancy were excluded. A total of 59 patients aged 18\u0026ndash;83 years who met the inclusion criteria were evaluated and assigned to three groups: SA (n\u0026thinsp;=\u0026thinsp;23), IA (n\u0026thinsp;=\u0026thinsp;18), and OA (n\u0026thinsp;=\u0026thinsp;18).\u003c/p\u003e \u003cp\u003eJoint aspiration was performed based on patient positioning: in the supine position, aspiration was performed from the patellofemoral joint, and in the seated position, from the femorotibial compartment. Prior to aspiration, the injection site was sterilized with 10% povidone-iodine and allowed to sit for 2 min. The procedure was performed using 18G or 21G spinal needles.\u003c/p\u003e \u003cp\u003eSF samples were first processed in the microbiology laboratory of the Center for Culture and Gram staining. Each sample was inoculated into BacT/ALERT FA Plus aerobic bottles (bioM\u0026eacute;rieux, France) and incubated using at BD BACTEC Fx automated system (Becton, Dickinson and Company, USA). Positive signals were subcultured on 5% sheep blood agar (RTA, Turkey) and MacConkey agar (RTA, Turkey), and evaluated after 18\u0026ndash;24 h of incubation at 37\u0026deg;C. Identification and susceptibility testing of microorganisms were performed using conventional methods and at BD Phoenix 100 automated system (Becton, Dickinson and Company, USA).\u003c/p\u003e \u003cp\u003eThe SF samples remaining after microbiological evaluation were stored at -80\u0026deg;C. On the day of analysis, the samples were thawed at room temperature in a single-step process to minimize contamination. CRP levels were measured using an immunoturbidimetric assay with an Alinity c analyzer (Abbott Laboratories, USA), and the same samples were used for PRGN measurement by ELISA. PRGN concentrations were determined in accordance with the manufacturer\u0026rsquo;s instructions using an ELISA kit (BT LAB, Shanghai Korain Biotech Co., Ltd., China) and are reported in ng/mL.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe normality of the numerical variables was assessed using the Kolmogorov\u0026ndash;Smirnov test. As parametric assumptions were not met, comparisons between groups were performed using the Kruskal\u0026ndash;Wallis test, and pairwise comparisons were conducted using the Mann\u0026ndash;Whitney U test. Categorical variables were analyzed using the chi-square test.\u003c/p\u003e \u003cp\u003eReceiver Operating Characteristic (ROC) curve analysis was used to assess the discriminatory ability of the variables. Diagnostic accuracy was evaluated using ROC curves, and optimal cut-off values were determined using the Youden Index. The area under the curve (AUC) values were reported with 95% confidence intervals (CI). ROC analysis was conducted separately for SF-CRP and SF-PRGN to assess their performance in distinguishing SA from IA and OA, respectively. The resulting AUC values were used to determine the diagnostic accuracy of each biomarker. Diagnostic performance parameters including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Logistic regression analysis was used for the multivariate analysis. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using IBM SPSS Statistics version 23 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 59 patients who met the inclusion criteria were enrolled and categorized into three groups: SA (n\u0026thinsp;=\u0026thinsp;23), IA (n\u0026thinsp;=\u0026thinsp;18), and OA (n\u0026thinsp;=\u0026thinsp;18). The mean ages were 50.7\u0026thinsp;\u0026plusmn;\u0026thinsp;18.5 years in the SA group, 46.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4 years in the IA group, and 52.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2 years in the OA group. There were no statistically significant differences between the groups in terms of age or sex (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Demographic and clinical characteristics of the study groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\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\u003eDemographic, Clinical, and Laboratory Characteristics of Patients with Septic Arthritis, Inflammatory Arthritis, and Osteoarthritis. Pairwise Comparisons of SF-CRP and SF-Prgn Levels in Different Study Groups\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c6\" namest=\"c3\"\u003e \u003cp\u003eGroups\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eCulture (-) SA (n\u0026thinsp;=\u0026thinsp;13)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMedian (Min-Max)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eCulture (+) SA (n\u0026thinsp;=\u0026thinsp;10)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMedian (Min-Max)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eIA (n\u0026thinsp;=\u0026thinsp;18)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMedian (Min-Max)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eOA (n\u0026thinsp;=\u0026thinsp;18)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003eMedian (Min-Max)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \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\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e0.287\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\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 \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.54\u0026thinsp;\u0026plusmn;\u0026thinsp;17.75\u003c/p\u003e \u003cp\u003e49 (27\u0026ndash;81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47\u0026thinsp;\u0026plusmn;\u0026thinsp;19.79\u003c/p\u003e \u003cp\u003e44.5 (21\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e46.56\u0026thinsp;\u0026plusmn;\u0026thinsp;11.41\u003c/p\u003e \u003cp\u003e43 (31\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e52.83\u0026thinsp;\u0026plusmn;\u0026thinsp;18.24\u003c/p\u003e \u003cp\u003e51.5 (14\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.542\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSF-CRP (mg/L)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.41\u0026thinsp;\u0026plusmn;\u0026thinsp;34.72\u003c/p\u003e \u003cp\u003e64.2 (0-108.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.37\u0026thinsp;\u0026plusmn;\u0026thinsp;60.13\u003c/p\u003e \u003cp\u003e69.75 (0-188.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18.97\u0026thinsp;\u0026plusmn;\u0026thinsp;18.17\u003c/p\u003e \u003cp\u003e18.25 (0-60.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.53\u0026thinsp;\u0026plusmn;\u0026thinsp;2.31\u003c/p\u003e \u003cp\u003e0.5 (0-8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSF-Prgn (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e330.37\u0026thinsp;\u0026plusmn;\u0026thinsp;156.2\u003c/p\u003e \u003cp\u003e294.07 (165.32-726.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e351.99\u0026thinsp;\u0026plusmn;\u0026thinsp;128.76\u003c/p\u003e \u003cp\u003e333.59 (168.75-523.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e300.52\u0026thinsp;\u0026plusmn;\u0026thinsp;159.6\u003c/p\u003e \u003cp\u003e296.39 (92.43-793.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e133.44\u0026thinsp;\u0026plusmn;\u0026thinsp;41.77\u003c/p\u003e \u003cp\u003e130.02 (52.79-211.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e*: The sex variable was analyzed using the Chi-square test.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u0026dagger;: Continuous variables were analyzed using the Kruskal\u0026ndash;Wallis test.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eSynovial fluid culture was positive in 10 of 23 patients (43.5%) in the SA group. The most frequently isolated microorganisms were Staphylococcus aureus (26.1%), Streptococcus spp. (4.3%), Staphylococcus epidermidis (4.3%), Klebsiella pneumoniae (4.3%), and Group A beta-hemolytic Streptococcus (4.3%). The remaining 13 patients (56.5%) in the SA group showed culture-negative results, whereas all synovial fluid samples from the IA and OA groups were sterile.\u003c/p\u003e \u003cp\u003eSignificant differences were observed among the groups in terms of the SF-PRGN and SF-CRP levels. The SA group was further subdivided into culture-positive (SA[+]) and culture-negative (SA[\u0026ndash;]). The mean SF-PRGN levels were 330.37\u0026thinsp;\u0026plusmn;\u0026thinsp;156.2 ng/mL in the SA(\u0026ndash;) subgroup, 351.99\u0026thinsp;\u0026plusmn;\u0026thinsp;128.76 ng/mL in the SA(+) subgroup, 300.52\u0026thinsp;\u0026plusmn;\u0026thinsp;159.60 ng/mL in the IA group, and 133.44\u0026thinsp;\u0026plusmn;\u0026thinsp;41.77 ng/mL in the OA group. The corresponding SF-CRP levels were 61.91\u0026thinsp;\u0026plusmn;\u0026thinsp;46.84 mg/L in SA, 18.97\u0026thinsp;\u0026plusmn;\u0026thinsp;18.17 mg/L in IA, and 1.64\u0026thinsp;\u0026plusmn;\u0026thinsp;2.25 mg/L in OA.\u003c/p\u003e \u003cp\u003eThe Kruskal\u0026ndash;Wallis test was used for group comparisons of continuous variables, followed by post hoc analyses for variables showing significant differences. The results of the post hoc comparisons are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, and the graphical distribution of SF-PRGN and SF-CRP levels across all groups is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. SF-CRP levels were significantly higher in the SA group than in both IA and OA groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both). No statistically significant difference was observed in the SF-PRGN levels between the SA and IA groups (p\u0026thinsp;=\u0026thinsp;0.803); however, the levels in the OA group were significantly lower than those in the SA and IA groups (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both). Subgroup analysis revealed no significant differences in SF-CRP and SF-PRGN levels between the culture-positive and culture-negative SA patients (p\u0026thinsp;=\u0026thinsp;0.983 and p\u0026thinsp;=\u0026thinsp;0.999, respectively).\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\u003ePairwise comparisons of SF-CRP and SF-Prgn levels among study groups using Tamhane\u0026rsquo;s T2 post hoc test\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroups Compared\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSF-CRP (p)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSF-Prgn (p)\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\u003eSA vs IA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.803\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIA vs OA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.004\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSA vs OA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSA(-) vs SA(+)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSA(-) vs. IA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.018\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.996\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSA(-) vs OA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.003\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSA(+) vs IA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.933\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSA(+) vs OA\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e.032\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.002\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e**: p\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe diagnostic performance analyses of SF-CRP and SF-PRGN are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The diagnostic accuracy of SF-CRP for differentiating SA from IA was high, with an AUC of 0.795 (95% CI: 0.640\u0026ndash;0.905, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The optimal cut-off value was \u0026gt;\u0026thinsp;50.4 mg/L, with a sensitivity of 60.87% and specificity of 94.44%. For SF-PRGN, ROC analysis yielded an AUC of 0.585 for distinguishing SA from IA, which was not statistically significant (p\u0026thinsp;=\u0026thinsp;0.3603). Using a cutoff value of \u0026gt;\u0026thinsp;458.46 ng/mL, the sensitivity was 30.43%, and the specificity was 94.44%. For differentiating SA from OA, the AUC values were 0.923 (95% CI: 0.795\u0026ndash;0.983, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and 0.971 (95% CI: 0.864\u0026ndash;0.999, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) for the SF-PRGN.\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\u003eDiagnostic Performance of SF-CRP and SF-Prgn in Differentiating SA, IA, and OA: ROC Curve Analysis.\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 \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAUC (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCut-off Value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSensitivity (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSpecificity (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF-CRP (SA vs IA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.795\u003c/p\u003e \u003cp\u003e(0.640\u0026ndash;0.905)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;50.4 mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF-Prgn (SA vs IA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.585\u003c/p\u003e \u003cp\u003e(0.420\u0026ndash;0.760)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;458.46 ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e94.44\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF-CRP (SA vs OA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.923\u003c/p\u003e \u003cp\u003e(0.795\u0026ndash;0.983)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;8.2 mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e86.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF-Prgn (SA vs OA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.971\u003c/p\u003e \u003cp\u003e(0.864\u0026ndash;0.999)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;171.07 ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e88.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF-CRP (IA vs OA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.802\u003c/p\u003e \u003cp\u003e(0.636\u0026ndash;0.916)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;8.2 mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e66.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e100.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF-Prgn (IA vs OA)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.880\u003c/p\u003e \u003cp\u003e(0.728\u0026ndash;0.964)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;171.07 ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e83.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e88.89\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 \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study compared the diagnostic performance of synovial fluid CRP and PRGN levels in patients with SA, IA, and OA, focusing on their ability to distinguish between SA and IA. Our findings revealed that while SF-PRGN levels were significantly elevated in both the SA and IA groups compared to OA, they did not differ significantly between SA and IA. In contrast, SF-CRP levels demonstrated a high diagnostic accuracy in differentiating SA from IA, with significantly higher values observed in the SA group.\u003c/p\u003e \u003cp\u003ePRGN is a glycoprotein with anti-inflammatory and chondroprotective properties, and its expression has been shown to increase in various inflammatory arthropathies, typically linked to heightened immune activation and TNF-α mediated pathways (\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Based on this mechanism, a significant difference in SF-PRGN levels between SA and IA patients was expected. Although SF-PRGN levels were higher in SA patients than in IA patients, the difference was not statistically significant. Several factors might explain this outcome. First, chronic inflammatory arthritis such as RA and psoriatic arthritis, is characterized by persistent synovial proliferation and elevated inflammatory burden. These conditions may result in the activation or suppression of various cytokines, some of which may modulate PRGN expression via distinct mechanisms. In a systematic review comparing OA and IA, Wei et al. reported increased PRGN expression in both diseases, albeit at differing levels. This variation is attributed to the divergent cytokine pathways involved in each disease (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Second, although none of the patients with IA were under active immunosuppressive treatment during sample collection, some may have previously received such therapies. Given the long half-life and lasting biological effects of these agents, their residual influence on synovial cytokine responses and PRGN levels is plausible. Importantly, current evidence regarding the role of PRGN in septic arthritis remains limited. While several studies have evaluated PRGN in the context of IA and OA (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), to our knowledge, this is among the first studies to assess SF-PRGN levels specifically in patients with SA, providing a novel contribution to the literature. These findings may serve as a foundation for future studies of PRGN as a potential biomarker.\u003c/p\u003e \u003cp\u003eIn our study, the proportion of culture-negative SA cases (56.5%) was consistent with that in previous reports; however, this high rate poses a limitation in diagnostic accuracy (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The elevated SF-PRGN levels observed in both culture-positive and culture-negative SA patients suggest that PRGN may be upregulated by the inflammatory cytokine response triggered by the infectious process of SA rather than directly by bacterial proliferation. This observation supports the hypothesis that PRGN reflects the overall inflammatory response specific to SA independent of culture positivity.\u003c/p\u003e \u003cp\u003eAlthough various studies have investigated SF-CRP, few have assessed its diagnostic value in distinguishing SA, IA, and OA simultaneously. Zamani et al. found significantly higher SF-CRP levels in patients with IA than in OA (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Using a methodology similar to that of our study, Streit et al. reported the highest SF-CRP levels in SA, followed by IA and OA, which is consistent with our findings (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Rowe et al. also demonstrated elevated SF-CRP levels in patients with IA compared to those with OA (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThese findings collectively support the utility of SF-CRP as a reliable diagnostic marker for differentiating SA from IA and OA. The significant increase in CRP levels in SA may reflect its correlation with inflammation severity. On the other hand, SF-PRGN successfully distinguished inflammatory (SA and IA) from non-inflammatory (OA) conditions but showed lower diagnostic performance than CRP in separating SA from IA. This may indicate that CRP responds more specifically to infection-induced inflammation, whereas PRGN may increase in response to both infectious and non-infectious inflammatory stimuli.\u003c/p\u003e \u003cp\u003eThis study hads several limitations. First, the relatively small sample size may have limited the statistical power and generalizability of the findings. Second, the assessment was restricted to only two biomarkers\u0026mdash;CRP and PRGN, which may not fully capture the complexity of the inflammatory process. In particular, serial sampling of synovial fluid in patients with SA could provide insights into the dynamic changes in biomarker levels throughout the disease course.\u003c/p\u003e \u003cp\u003eIn conclusion, our results suggest that SF-CRP demonstrates high diagnostic accuracy in distinguishing SA from IA and OA, and may serve as a reliable marker of infection-associated inflammation. Although SF-PRGN levels were elevated in SA and demonstrated a high AUC (0.971) in distinguishing SA from OA, its performance in differentiating SA from IA was limited by its low sensitivity (30.43%) and lack of statistical significance. These findings suggest that PRGN may reflect the overall inflammatory activity rather than act as a specific marker for infection.\u003c/p\u003e \u003cp\u003eFuture studies with larger cohorts and prospective designs are warranted to elucidate the role of PRGN in differentiating SA from IA, particularly with careful control of clinical variables such as disease activity, treatment history, and timing of sample collection.\u003c/p\u003e"},{"header":"Declarations","content":"\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration:\u003c/strong\u003e Clinical trial number: not applicable.\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate:\u0026nbsp;\u003c/strong\u003eThe study protocol was approved by the Scientific Research Ethics Committee of SANKO University (Approval Number: 2024/6). Written informed consent was obtained from all participants and the study was conducted in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\n\u003cp\u003e \u003cstrong\u003eEthics Statement:\u003c/strong\u003e \u003cp\u003e All participants provided written informed consent before inclusion in the study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting Interests:\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no relevant financial or non-financial interests to disclose. This has also been indicated in the ICMJE Conflict of Interest Form.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eInformed Consent:\u003c/h2\u003e \u003cp\u003e Informed consent was obtained from all individual participants included in the study\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.S. conceptualized and designed the study, coordinated patient recruitment, performed the statistical analyses, and drafted the initial manuscript.İ.K. performed the microbiological analyses, including synovial fluid culture and laboratory processing, and contributed to data interpretation.F.A. contributed to the clinical evaluation of patients with inflammatory arthritis and participated in data collection.N.Y.S. contributed to the radiological evaluation and interpretation of imaging findings.\u0026Ccedil;.K. assisted in patient recruitment, joint aspiration procedures, and clinical data collection.B.K. supervised the study, contributed to the clinical interpretation of the results, and critically revised the manuscript for important intellectual content.All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDomagała A, Macura B, Piekarz K, Kiecka A. Septic arthritis\u0026ndash;symptoms, diagnosis and new therapy. Eur J Clin Microbiol Infect Dis. 2025:1\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoss JJ. Septic arthritis of native joints. Infect Disease Clin. 2017;31(2):203\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe Z, Bateman A. Progranulin (granulin-epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J Mol Med. 2003;81(10):600\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCerezo LA, Kuklov\u0026aacute; M, Hulejov\u0026aacute; H, Vernerov\u0026aacute; Z, Kaspř\u0026iacute;kov\u0026aacute; N, Veigl D, et al. Progranulin Is Associated with Disease Activity in Patients with Rheumatoid Arthritis. Mediators Inflamm. 2015;2015:740357.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen J, Li S, Shi J, Zhang L, Li J, Chen S, et al. Serum progranulin irrelated with Breg cell levels, but elevated in RA patients, reflecting high disease activity. Rheumatol Int. 2016;36:359\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJing C, Zhang X, Song Z, Zheng Y, Yin Y. Progranulin Mediates Proinflammatory Responses in Systemic Lupus Erythematosus: Implications for the Pathogenesis of Systemic Lupus Erythematosus. J Interferon Cytokine Res. 2020;40(1):33\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanaka A, Tsukamoto H, Mitoma H, Kiyohara C, Ueda N, Ayano M, et al. Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity. Arthritis Res therapy. 2012;14:1\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThurner L, Preuss KD, Fadle N, Regitz E, Klemm P, Zaks M, et al. Progranulin antibodies in autoimmune diseases. J Autoimmun. 2013;42:29\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamamoto Y, Takemura M, Serrero G, Hayashi J, Yue B, Tsuboi A, et al. Increased serum GP88 (Progranulin) concentrations in rheumatoid arthritis. Inflammation. 2014;37(5):1806\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDaynes J, Roth MF, Zekaj M, Hudson I, Pearson C, Vaidya R. Adult Native Septic Arthritis in an Inner City Hospital: Effects on Length of Stay. Orthopedics. 2016;39(4):e674\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe M, Arthur Vithran DT, Pan L, Zeng H, Yang G, Lu B, et al. An update on recent progress of the epidemiology, etiology, diagnosis, and treatment of acute septic arthritis: a review. Front Cell Infect Microbiol. 2023;13:1193645.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcBride S, Mowbray J, Caughey W, Wong E, Luey C, Siddiqui A, et al. Epidemiology, Management, and Outcomes of Large and Small Native Joint Septic Arthritis in Adults. Clin Infect Dis. 2019;70(2):271\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStirling P, Faroug R, Amanat S, Ahmed A, Armstrong M, Sharma P, et al. False-negative rate of gram-stain microscopy for diagnosis of septic arthritis: suggestions for improvement. Int J Microbiol. 2014;2014:830857.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei J, Hettinghouse A, Liu C. The role of progranulin in arthritis. Ann N Y Acad Sci. 2016;1383(1):5\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalinga AB, Stornebrink T, Langerhuizen DWG, Struijs PAA, Kerkhoffs GMMJ, Janssen SJ. What are the best diagnostic tests for diagnosing bacterial arthritis of a native joint? Bone Joint J. 2021;103\u0026ndash;B(12):1745\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZamani B, Jamali R, Ehteram H. Synovial fluid adenosine deaminase and high-sensitivity C-reactive protein activity in differentiating monoarthritis. Rheumatol Int. 2012;32(1):183\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStreit G, Alber D, Toussirot E, Wendling D, Toubin MM, Procalcitonin. C-reactive protein, and complement-3a assays in synovial fluid for diagnosing septic arthritis: Preliminary results. Joint Bone Spine. 2008;75(2):238\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRowe I, Sheldon J, Riches P, Keat A. Comparative studies of serum and synovial fluid C reactive protein concentrations. Ann Rheum Dis. 1987;46(10):721\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\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":"advances-in-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"adrh","sideBox":"Learn more about [Advances in Rheumatology](https://advancesinrheumatology.biomedcentral.com/)","snPcode":"42358","submissionUrl":"https://submission.springernature.com/new-submission/42358/3","title":"Advances in Rheumatology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Septic Arthritis, Inflammatory Arthritis, Progranulin, C-Reactive Protein, Synovial Fluid","lastPublishedDoi":"10.21203/rs.3.rs-9102472/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9102472/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeptic arthritis (SA) is a rapidly progressive joint disease that can lead to cartilage damage if not promptly treated. A prompt and accurate distinction between SA and inflammatory arthritis (IA) is essential to establish an optimal treatment plan. Progranulin (PRGN), an anti-inflammatory glycoprotein involved in various autoimmune diseases, has scarcely been studied as a diagnostic biomarker of infectious arthritis. Its precise role in this context remains to be elucidated. This study aimed to evaluate the diagnostic utility of synovial fluid PRGN (SF-PRGN) in distinguishing SA from IA and osteoarthritis (OA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis single-center, cross-sectional study included 59 patients who underwent synovial fluid aspiration and were categorized into three groups: SA (n = 23), IA (n = 18), and OA (n = 18). SA was diagnosed based on positive synovial fluid culture or fulfillment of clinical criteria suggestive of infection. SF-PRGN levels were measured using ELISA, and synovial fluid C-reactive protein (SF-CRP) levels were determined using an immunoturbidimetric assay.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMean SF-PRGN levels were higher in the SA (339.77 ± 142.16 ng/mL) and IA (300.52 ± 159.60 ng/mL) groups compared to the OA group (133.44 ± 41.77 ng/mL), indicating a statistically significant difference between inflammatory and non-inflammatory groups (p \u0026lt; 0.05). However, the SF-PRGN did not significantly differentiate between SA and IA (p = 0.803). In contrast, SF-CRP levels were markedly elevated in SA (61.91 ± 46.84 mg/L) and demonstrated a strong discriminatory power between SA and IA (p \u0026lt; 0.001; AUC: 0.795, p \u0026lt; 0.0001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough SF-PRGN was elevated in inflammatory arthritis, it lacked specificity for SA. SF-CRP showed superior diagnostic accuracy in differentiating SA from IA. These findings underscore the need for further research on reliable biomarkers for SA in larger patient cohorts.\u003c/p\u003e","manuscriptTitle":"Progranulin in the Differentiation of Septic and Inflammatory Arthritis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-22 05:46:38","doi":"10.21203/rs.3.rs-9102472/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-15T02:05:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T21:56:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T16:26:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"268248214954735645654742919095810474671","date":"2026-04-15T13:58:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"324849049219791074523163900600531249203","date":"2026-04-14T12:10:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-14T10:56:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-16T06:11:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-16T06:11:03+00:00","index":"","fulltext":""},{"type":"submitted","content":"Advances in Rheumatology","date":"2026-03-12T08:45:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"advances-in-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"adrh","sideBox":"Learn more about [Advances in Rheumatology](https://advancesinrheumatology.biomedcentral.com/)","snPcode":"42358","submissionUrl":"https://submission.springernature.com/new-submission/42358/3","title":"Advances in Rheumatology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eb544d52-460c-4cc4-9e40-8f6c87a32f5a","owner":[],"postedDate":"April 22nd, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-15T02:05:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-01T21:56:10+00:00","index":15,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T02:08:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-22 05:46:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9102472","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9102472","identity":"rs-9102472","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}