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Background: There are currently no effective disease-modifying drugs to prevent cartilage loss in osteoarthritis and synovial fluid is a potentially valuable source of biomarkers to understand the pathogenesis of different types of arthritis and identify drug responsiveness. The aim of this study was to compare the differences between SF cytokines and other proteins in patients with OA (n = 21) to those with RA (n = 27) and normal knees (n = 3). Methods: SF was obtained using ultrasound (US) guidance and an external pneumatic compression device. RA patients were categorized as active (n = 20) or controlled (n = 7) based upon SF white blood cell counts (> or <300 cells/mm3). Samples were cryopreserved and analyzed by multiplex fluorescent bead assays (Luminex). Between-group differences of 16 separate biomarker proteins were identified using ANOVA on log10-transformed concentrations with p values adjusted for multiple testing. Results: Only six biomarkers were significantly higher in SF from active RA compared to OA—TNF-α, IL-1-β IL-7, MMP-1, MMP-2, and MMP-3. Only MMP-8 levels in RA patients correlated with SF WBC counts (p < 0.0001). Among OA patients, simultaneous SF IL-4, IL-6, IL-8, and IL-15 levels were higher than serum levels, whereas MMP-8, MMP-9, and IL-18 levels were higher in serum (p < 0.05). Conclusion: These results support the growing evidence that OA patients have a pro-inflammatory/catabolic SF environment. SF biomarker analysis using multiplex testing and US guidance may distinguish OA phenotypes and identify treatment options based upon targeted inflammatory pathways similar to patients with RA.

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BackgroundPrior studies have demonstrated improved accuracy and efficacy when Intra-articular (IA) therapeutics are injected using ultrasound (US) guidance. There is also growing evidence that many patients with knee osteoarthritis (OA) exhibit a pro-inflammatory catabolic synovial fluid (SF) profile. However, it is not known if temporary clinical improvement in pain and function after IA Hyaluronic acid (HA) injections is associated with changes in SF volumes.ObjectivesThe purpose of this study was to determine if IA HA injections delivered using US directed needle visualization with an external pneumatic compression device would result in improved clinical outcomes for knee OA at 3 and 6 months, and if this was associated with a reduction in the amount of knee synovial fluid (SF) measured on US.Methods49 eligible subjects with symptomatic Knee OA, BMI < 40 and KL radiographic rating of II or III OA were consented for this open label prospective IRB approved Investigator Initiated SF OA biomarker study (HS 3179, NCT 04093232). All standing radiographs were reviewed by a fellowship-trained MSK radiologist. 36 subjects had adequate aspirated SF volumes of > 500 mcl for biomarker analysis and therefore were eligible to receive two IA injections of HYADD4, 24 mg/3ml (Fidia Farmaceutici S.p.A. Italy) 7 days apart by a MSK US certified Rheumatologist. An external pneumatic compression device and US visualized needle insertion ensured injections were delivered into the intra-synovial space. Despite COVID-19 restrictions, 34 patients (17 women and 17 men) between 35 and 78 years of age returned for 3 month evaluations and 30 had evaluations at 6 months. The following clinical variables were measured: Western Ontario and McMaster Universities Index (WOMAC) total scores, Visual Analog Pain Scale (VAS, 0-10), PCS scores on the SF-36 health survey questionnaires (physical function/bodily pain and general health), 6-minute walking distance in meters (6 MWD), and measured SF depth before and after an external pneumatic compression device was inflated to 100 mmHg to facilitate aspiration by increasing available SF volumes under positive presure. The SF depth was measured on the recorded US image (GE logiq e) as the largest anechoic region selected for aspiration on either the lateral (n= 30) or medial (n=4) compartment. SF and simultaneous peripheral blood samples were centrifuged and cryopreserved at -80 o C within 45 minutes of aspiration for future analysis. Statistical differences between baseline values compared to those levels at 3 and 6 months were determined using a paired ANOVA test with p <0.05 significance.ResultsImprovements over baseline values were observed at 3 and 6 months respectively, after IA HA injections in WOMAC (40%, 40%), VAS (45%, 51%) and PCS (15%, 18%) all p< 0.0001. The 6 WWD improved by 7 % at 3 months (p< 0.007) but was not statistically improved at 6 months. US measured SF depth at baseline was 3.2 ± 2.2 mm before inflation and 6.4 + 3.7 mm after inflation of the pneumatic external compressioin device but statistical differences in SF depth were not observed at 3 and 6 months.ConclusionDespite improvements in WOMAC, VAS scores, and PCS scores on the SF 36 at 3 and 6 months after US guided knee injections with an HA product, a statistically significant reduction in the amount of US measured SF was not observed. The 6 MWD improved at 3 months but was not statistically different from the baseline distance by 6 months. IA injections using US needle visualization confirmed that the product was delivered into the synovial space with 100 % accuracy which might have resulted in improved efficacy results in this study compared to prior IA HA studies injected without US or using different HA products. In the future, we hope SF biomarkers may identify which individual OA patients will likely achieve the greatest benefit with IA HA injections and to determine if this is associated with a reduction in catabolic pro-inflammatory proteins.Disclosure of Interestsrichard Meehan Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. I was the PI., Mary Gill Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As the study coordinator she received salary support, Eric Hoffman Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As a biomedical engineer consultant he received some compensation for his work., Molly Wolf Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As the Immunology laboratory supervisor she received support from this grant for sample processing and analysis., Isabelle Amigues Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As a Rheumatologist who performed some of the aspirations and injections she did receive some very small salary support from this grant., Liudmila (Mila) Kastsianok Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As a Rheumatologist who performed some of the aspirations and injections she did receive some very small salary support from this grant., Elizabeth Regan Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As a orthopedic surgeon and immunologists she did receive some very small salary support from this grant., James Crooks Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As our biostatistician for this project he did receive some support from this grant for statistical analysis and consultation., Gregory Czuczman: None declared, claire Coeshott Consultant of: She was ben an employee for pharmaceutical companies in the past unrelated to this project and has no relationship in the past with Fidia who funded the study., Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As the director of the ADx immunology labs where this samples are processed her staff received some compensation for sample handling and biomarker analysis. She did not receive any salary support., Vijaya Knight Grant/research support from: This grant was funded by Fidia Pharmaceutici and Fidia Pharma USA as an Investigator Initiated grant for synovial fluid based biomarker research in osteoarthritis. As an Immunologists and prior director of the ADx immunology labs when the project started in 2019 her staff performed sample processing and testing and they received support from this grant by Dr Knight did not receive and salary support or direct compensation for her consultation expertise.