Intra-articular Administration Research Articles

Angiotensin type 2 receptor antagonism as a new target to manage gout.

There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1β release, mRNA expression analyses and nitrite/nitrate levels, 4h after injections. AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1β levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1β levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.

Development and Evaluation of Novel Leflunomide SPION Bioemulsomes for the Intra-Articular Treatment of Arthritis.

Systemic treatments for rheumatoid arthritis are associated with many side effects. This study aimed to minimize the side effects associated with the systemic administration of leflunomide (LEF) by formulating LEF-loaded emulsomes (EMLs) for intra-articular administration. Additionally, EMLs were loaded with supramagnetic nanoparticles (SPIONs) to enhance joint localization, where a magnet was placed on the joint area after intra-articular administration. Full in vitro characterization, including colloidal characteristics, entrapment efficiency, and in vitro release were conducted besides the in vivo evaluation in rats with adjuvant-induced arthritis. In vivo study included joint diameter measurement, X-ray radiographic analysis, RT-PCR analysis, Western blotting, ELISA for inflammatory markers, and histopathological examination of dissected joints. The particle size and entrapment efficiency of the selected LEF SPION EMLs were 198.2 nm and 83.7%, respectively. The EMLs exhibited sustained release for 24 h. Moreover, in vivo evaluation revealed LEF SPION EMLs to be superior to the LEF suspension, likely due to the increase in LEF solubility by nanoencapsulation that improved the pharmacological effects and the use of SPION that ensured the localization of EMLs in the intra-articular cavity upon administration.

The value of injectable viscoelastic supplements for joints.

Intra-articular viscoelastic supplements are commonly administered by musculoskeletal radiologists for the treatment of symptomatic osteoarthritis (OA). This article provides an overview of the putative mechanism of action of the agents, a brief review of the evidence base underlying the practice, a commentary on some of the major society guidelines regarding the treatment, and a description of the adverse events that are associated with intra-articular hyaluronic acid administration.

Intravenous injection of adipose-derived mesenchymal stromal cells benefits gait and inflammation in a spontaneous osteoarthritis model.

Osteoarthritis (OA) is a leading cause of morbidity among aging populations, yet symptom and/or disease-modification remains elusive. Adipose-derived mesenchymal stromal cells (adMSCs) have demonstrated immunomodulatory and anti-inflammatory properties that may alleviate clinical signs and interrupt disease onset and progression. Indeed, multiple manuscripts have evaluated intra-articular administration of adMSCs as a therapeutic; however, comparatively few evaluations of systemic delivery methods have been published. Therefore, the aim of this study was to evaluate the short-term impact of intravenous (IV) delivery of allogeneic adMSCs in an established model of spontaneous OA, the Hartley guinea pig. Animals with moderate OA received once weekly injections of 2 × 106 adMSCs or vehicle control for 4 weeks in peripheral veins; harvest occurred 2 weeks after the final injection. Systemic administration of adMSCs resulted in no adverse effects and was efficacious in reducing clinical signs of OA (as assessed by computer-aided gait analysis) compared to control injected animals. Further, there were significant decreases in key inflammatory mediators (including monocyte chemoattractant protein-1, tumor necrosis factor, and prostaglandin E2 ) both systemically (liver, kidney, and serum) and locally in the knee (joint tissues and synovial fluid) in animals treated with IV adMSCs relative to controls (as per enzyme-linked immunosorbent assay and/or immunohistochemistry, dictated by tissue sample). Thus, systemic administration of adMSCs by IV injection significantly improved gait parameters and reduced both systemic and intra-articular inflammatory mediators in animals with OA. These findings demonstrate the potential utility of alternative delivery approaches for cellular therapy of OA, particularly for patients with multiple affected joints.

Nanoarchitectonics of Cartilage-Targeting Hydrogel Microspheres with Reactive Oxygen Species Responsiveness for the Repair of Osteoarthritis

Clinically, intra-articular administration can hardly achieve the truly targeted therapy, and the drugs are usually insufficient to show local and long-term therapeutic effects because of their rapid clearance. Herein, inspired by the phenomenon that bees track the scent of flowers to collect nectar, we developed cartilage-targeting hydrogel microspheres with reactive oxygen species (ROS)-responsive ability via combining the microfluidic method and photopolymerization processes to integrate cartilage-targeting peptides and ROS-responsive nanoparticles in the hydrogel matrix. The hydrogel microspheres with cartilage-targeting properties promoted better retention in the joint cavity and enhanced cellular uptake of the nanoparticles. Moreover, the ROS-responsive nanoparticles could react with osteoarthritis (OA)-induced intracellular ROS, resulting in the depolymerization of nanoparticles, which could not only eliminate excess ROS and reduce inflammation but also promote the release of dexamethasone (Dex) and kartogenin (KGN) in situ, realizing effective OA therapy. It was demonstrated that this hydrogel microsphere showed favorable ROS-responsive ability and enhanced chondrogenic differentiation as well as the downregulation of pro-inflammatory factors in vitro. Additionally, the hydrogel microspheres, similar to bees, could target and effectively repair cartilage in the OA model. Thus, the injectable hydrogel microspheres exerted an excellent potential to repair OA and may also provide an effective avenue for inflammatory bowel disease therapy.

1486MO The synovial and systemic pharmacokinetics and pharmacodynamics of intra-articular administration of the CSF1 receptor antibody AMB-05X in a phase II proof-of-concept trial in tenosynovial giant cell tumor

It is well established that CSF1 action at the CSF1R mediates the formation and expansion of TGCT – a benign but locally aggressive neoplasm. Indeed, oral or intravenous administration of CSF1R inhibitors may yield tumor regression over weeks to months of repeat dosing. With these systemic exposures, on-target side effects such as liver enzyme elevation and facial edema often present and may complicate the treatment paradigm. We hypothesized that administration of a potent, inhibitory anti-CSF1R antibody, AMB-05X, into the affected synovium could yield sustained, high local concentrations with low systemic exposures and thus enable tumor regression with minimal pharmacologic side effects. 8 TGCT patients with confirmed TGCT of the knee were enrolled in a Phase 2 study wherein AMB-05X was administered intra-articular (IA) at a dose of 150 mg every 2 weeks over a 12-week treatment period. The synovial and serum pharmacokinetics of AMB-05X were monitored. CSF1 levels in the joint and serum were also quantitated as a pharmacodynamic marker since inhibitor action at the CSF1R interferes with native and tumor-derived CSF1 elimination. The clearance of antibodies administered intra-articular is not well characterized and, in fact, has often been regarded as short-lived. The unique formulation of AMB-05X administered at the dose and regimen employed in this proof-of-concept study yielded high local concentrations that were sustained beyond expectations such that accumulation over the dosing period was extensive (>5-fold). Importantly, systemic exposures were consistently approximately 1/5 that of the synovial concentrations. Moreover, pharmacodynamic elevation of CSF1 levels was approximately 20-fold greater in synovial fluid vs serum. CSF1 levels in both compartments achieved a plateau, indicative of full receptor engagement, early in the treatment period. The AMB-05X PK and PD results support expansion of the clinical development of AMB-05X in TGCT with IA treatment at a comfortable interval of once-monthly or less.

Autologous Stem Cells Transplants in the Treatment of Temporomandibular Joints Disorders: A Systematic Review and Meta-Analysis of Clinical Trials.

This systematic review aims to analyze the outcomes of the treatment of temporomandibular joint (TMJ) articular pain (AP) and restricted maximum mouth opening (MMO) with intra-articular administration of mesenchymal stem cells (MSCs). The inclusion criteria allowed primary studies involving AP and/or MMO pre-treatment and post-intervention values. Medical databases that were covered by ACM Digital, BASE, EBSCOhost, Google Scholar, PubMed, Scopus, and Web of Science engines were searched. The risk of bias was assessed with RoB 2 and ROBINS-I tools. The results were tabulated, plotted, and analyzed for regression. A total of 5 studies involving 51 patients/69 TMJs were identified, and 4 studies on 50 patients/67 TMJs were synthesized. Interventions were each time effective in decreasing AP and increasing MMO in a 6-month follow-up period by an average of about 85% and over 40%, respectively. Regression analysis showed a good fit of the logarithmic model for AP relief (5.8 − 0.8 ln x; R2 = 0.90) and MMO increase (33.5 + 2.4 ln x; R2 = 0.89). The results for AP and MMO were based on 3 studies in 39 patients and 4 studies in 50 patients, respectively, all at high risk of bias. The intra-articular administration of MSCs to TMJs, based on weak evidence, may be highly effective in reducing AP and improving MMO. This study received no funding.

Pharmacotherapy of pain in musculoskeletal diseases: evolution and revolution of views

The article presents new views on the treatment of pain syndromes in musculoskeletal diseases, in particular in osteoarthritis (OA) of various localizations (gonarthrosis, coxarthrosis). New recommendations (2019–2020) of international societies for the study of symptomatic delayedacting drugs (SYSADOA) and their use in the treatment of OA are presented. We present the opinions of experts from different communities: the American College of Rheumatology (ACR, 2019), the European Alliance of Associations for Rheumatology (EULAR, 2019), the European Society for the Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO, 2020) – on the prescription of SYSADOA, which include chondroitin sulfate (CS), glucosamine sulfate (GS), avocado and soy unsaponifiable compounds, diacerein, hyaluronic acid for intraarticular administration. New domestic clinical guidelines (2020–2021) for the treatment of OA are presented. The changes that have taken place in the terminology of pain and in the classification of pain syndromes, reflected in the new International Classification of Diseases of the 11 th revision (ICD-11), are analyzed. New approaches to the stratification of OA, taking into account endo- and phenotyping, as well as new aspects in pain therapy associated with the molecular genetic mechanisms of SYSADOA are shown. According to the EULAR recommendations, there is indisputable evidence of the efficacy and safety of pharmaceutical CS, which is reflected in a meta-analysis (2019), a randomized placebo-controlled trial (2019), approved by the Russian Ministry of Health, and confirmed in Chondroguard’s meta-analysis of clinical trials (2020). New approaches in the treatment of pain syndromes provide for parenteral administration of CS and GS according to an intermittent scheme. The search and development of new molecules comparable in efficacy to SYSADOA in the treatment of pain in OA and low back pain have led to the emergence in clinical practice of biologically active compositions, including undenatured type II collagen, the effectiveness of which is associated with a neuroimmune mechanism of action.

A first report on the efficacy of a single intra-articular administration of blood cell secretome, triamcinolone acetonide, and the combination of both in dogs with osteoarthritis

BackgroundOsteoarthritis represents a significant welfare problem for many dogs, with limited therapeutic options other than palliative pain control. To evaluate the effect of the intra-articular administration of blood cell secretome and triamcinolone, 15 dogs with bilateral hip osteoarthritis were randomly assigned to a blood cell secretome (BCSG, n = 5), triamcinolone (TG) or their combination group (BCS + TG, n = 5). BCSG received a single intra-articular administration of 3 ml of blood cell secretome, TG 0.5 ml of triamcinolone acetonide 40 mg/ml, and BCS + TG received the combined products. The volume to administrate was corrected to 3.5 ml with saline. On days 0, 8, 15, 30, 60, 90, 120, 150, and 180, a copy of the Canine Brief Pain Inventory (divided into pain interference score—PIS and Pain Severity Score—PSS), Liverpool Osteoarthritis in Dogs (LOAD), Hudson Visual Analogue Scale (HVAS), and Canine Orthopedic Index (COI, divided into function, gait, stiffness, and quality of life) was completed. Results were analyzed with the Kruskal–Wallis test and the Kaplan–Meier estimators were conducted and compared with the Log Rank test, p < 0.05.ResultsAnimals in the sample had a mean age of 9.0 ± 2.9 years and a bodyweight of 28.8 ± 4.1 kg. Hips were classified as moderate (8) and severe (7) osteoarthritis. No differences were found between groups at T0 regarding considered evaluations. Significant differences were observed between groups in pain scores from + 8d- + 150d, with BCS + TG exhibiting better results. The same was observed for HVAS and LOAD, from + 8d- + 120d. Improvements were also observed in several dimensions of the COI. Kaplan–Meier estimators showed that BCS + TG produced longer periods with better results, followed by BCSG and TG.ConclusionThe intra-articular administration of blood cell secretome improved the clinical signs and scores of several clinical metrology instruments in dogs with hip OA, particularly when combined with triamcinolone. Further studies are required.

Changes in the number of white blood cells and non-specific markers of inflammation in the body of rabbits in experimental osteoarthritis of the knee joint

Osteoarthritis is the most common joint disease in animals, which is not always treatable. Both in veterinary and in human medicine, laboratory research methods are used to effectively diagnose this pathology. The purpose of this study was to establish the dynamics of markers of the acute phase of inflammation in the blood using experimental modelling of knee osteoarthritis in rabbits. Artificial reproduction of the pathological process in the knee joints of animals was performed by intra-articular administration of Yellow peel 2*5 ml. The BC-2800Vet automatic haematology analyser (China) was used to calculate the number of white blood cells and their subpopulations in the blood. The content of C-reactive protein in blood serum was found using enzyme-linked immunosorbent assay. The rate of erythrocyte sedimentation in the blood was investigated according to the Panchenkov method. Thus, on Day 7, a sharp increase in the number of white blood cells (2.7 times) and their subpopulations was noted in sick rabbits, which indicates an active inflammatory process of a systemic nature. On Day 14, their number in the blood of sick animals was characterized by a tendency to decrease, but it had not yet reached the values of the control group. On Days 21 and 28, all the indicators under study tended to decrease in sick animals. Specifically, the number of white blood cells and their subpopulations acquired reference values. The content of C-reactive protein significantly increased by 40.8 times in sick animals on Day 7 of the study and decreased by 1.7 times on Day 14 compared to its values at the previous stage. At the same time, on Day 28, this indicator increased by 19.3 times compared to the indicators of the control group of animals. The rate of erythrocyte sedimentation in the blood of sick rabbits significantly increased by 2.3 times compared to the control group. On Day 21, this indicator in the blood of sick rabbits decreased by 1.4 times compared to its values on Day 14 of the experiment. On the other hand, on Day 28, its value increased by 1.7 times compared to the control (4.3 mm/h). The results obtained will contribute to further targeted laboratory diagnostics of knee osteoarthritis in animals, which will ensure the proper effectiveness of therapeutic and preventive measures and improve their overall health

Thermosensitive Injectable Hydrogels for Intra-Articular Delivery of Etanercept for the Treatment of Osteoarthritis.

The intra-articular administration of drugs has attracted great interest in recent decades for the treatment of osteoarthritis. The use of modified drugs has also attracted interest in recent years because their intra-articular administration has demonstrated encouraging results. The objective of this work was to prepare injectable-thermosensitive hydrogels for the intra-articular administration of Etanercept (ETA), an inhibitor of tumor necrosis factor-α. Hydrogels were prepared from the physical mixture of chitosan and Pluronic F127 with β-glycerolphosphate (BGP). Adding β-glycerolphosphate to the system reduced the gelation time and also modified the morphology of the resulting material. In vitro studies were carried out to determine the cytocompatibility of the prepared hydrogels for the human chondrocyte line C28/I2. The in vitro release study showed that the incorporation of BGP into the system markedly modified the release of ETA. In the in vivo studies, it was verified that the hydrogels remained inside the implantation site in the joint until the end of the study. Furthermore, ETA was highly concentrated in the blood of the study mice 48 h after the loaded material was injected. Histological investigation of osteoarthritic knees showed that the material promotes cartilage recovery in osteoarthritic mice. The results demonstrate the potential of ETA-loaded injectable hydrogels for the localized treatment of joints.

Repeated Intra-Articular Administration of Platelet-Rich Plasma (PRP) in Temporomandibular Disorders: A Clinical Case Series.

Background: Temporomandibular joint disorders (TMDs) are manifested, inter alia, by pain and limited scope of the mandibular abduction. Among the treatment strategies for these ailments, intra-articular injections of autologous blood preparations, including platelet-rich plasma (PRP), are administered. This prospective case series was aimed at assessing the effectiveness of repeated platelet-rich plasma (PRP) administration to the TMJ cavities in terms of reducing articular pain and increasing the mobility of the mandible. Material and methods: 40 consecutive patients diagnosed with TMJ pain qualified for the case series. The entire treatment program consisted of five PRP administrations and a summary appointment. Regression was analyzed for (1) intensity of spontaneous pain; (2) effectiveness of spontaneous pain relief; (3) mastication efficiency values; (4) painless mandibular abduction; (5) maximum mouth opening. The correlations between the abovementioned variable series were analyzed. Results: The mean spontaneous pain decreased consistently with successive PRP administrations in line with the regression model: −0.4x + 4.2 (R2 = 0.98). Articular pain improvement was reported in 71% of joints treated. Improvement in chewing quality at the end of the entire injection cycle was found in 63% of patients. The equations for the linear regression models for painless mandibular abduction (five applications of PRP) and maximum mouth opening (the first four applications of PRP) were x + 34 (R2 = 0.89) and 0.6x + 43.6 (R2 = 0.96), respectively. Improvement in these domains was found in 78% and 53% of patients, respectively. The strongest correlations were found between pain and chewing efficiency (−0.95), pain and painless mandible abduction (−0.96), and painless mandibular abduction and mastication efficiency (0.94). Conclusion: PRP injections into TMJ cavities should be considered as a low invasive, highly accessible form of treatment for various TMDs causing pain and mandible movement limitation.

Cationic peptide carriers enable long-term delivery of insulin-like growth factor-1 to suppress osteoarthritis-induced matrix degradation

BackgroundInsulin-like growth factor-1 (IGF-1) has the potential to be used for osteoarthritis (OA) treatment but has not been evaluated in clinics yet owing to toxicity concerns. It suffers from short intra-joint residence time and a lack of cartilage targeting following its intra-articular administration. Here, we synthesize an electrically charged cationic formulation of IGF-1 by using a short-length arginine-rich, hydrophilic cationic peptide carrier (CPC) with a net charge of +14, designed for rapid and high uptake and retention in both healthy and arthritic cartilage.MethodsIGF-1 was conjugated to CPC by using a site-specific sulfhydryl reaction via a bifunctional linker. Intra-cartilage depth of penetration and retention of CPC-IGF-1 was compared with the unmodified IGF-1. The therapeutic effectiveness of a single dose of CPC-IGF-1 was compared with free IGF-1 in an IL-1α-challenged cartilage explant culture post-traumatic OA model.ResultsCPC-IGF-1 rapidly penetrated through the full thickness of cartilage creating a drug depot owing to electrostatic interactions with negatively charged aggrecan-glycosaminoglycans (GAGs). CPC-IGF-1 remained bound within the tissue while unmodified IGF-1 cleared out. Treatment with a single dose of CPC-IGF-1 effectively suppressed IL-1α-induced GAG loss and nitrite release and rescued cell metabolism and viability throughout the 16-day culture period, while free IGF at the equivalent dose was not effective.ConclusionsCPC-mediated depot delivery of IGF-1 protected cartilage by suppressing cytokine-induced catabolism with only a single dose. CPC is a versatile cationic motif that can be used for intra-cartilage delivery of other similar-sized drugs.

Poster 268: Allogeneic, Off The Shelf, Bone Marrow derived, Pooled, Mesenchymal Stromal Cells – A Potential Break through Therapy for Grade II &amp; III Osteoarthritis Knee Management

Poster 268: Allogeneic, Off The Shelf, Bone Marrow derived, Pooled, Mesenchymal Stromal Cells – A Potential Break through Therapy for Grade II &amp; III Osteoarthritis Knee Management

Poster 102: Assessment of Safety and Efficacy of Intravenous and Intraarticular Administration of Tranexamic Acid in Arthroscopic Surgery: A Systematic Review of Randomized Controlled Trials

Objectives:Tranexamic acid (TXA) is widely used in arthroplasty procedures and has recently gained popularity as an adjunct for improving perioperative outcomes after arthroscopic procedures. However, the safety, side-effect profile, and efficacy of various routes of administration (intravenous and intraarticular) of tranexamic acid in arthroscopic surgery have not been clearly delineated. The objectives of this study are to analyze the available literature on overall safety, efficacy, and complications such as deep vein thrombosis, pulmonary embolus, and infection following administration of intravenous (IV) or intraarticular (IA) tranexamic acid in arthroscopic procedures.Methods:A literature search in agreement with the Preferred Reporting Items from Systematic Reviews and Meta-Analyses (PRISMA) protocol was performed to retrieve randomized controlled trials examining the use of tranexamic acid at the time of arthroscopic procedures. Inclusion criteria included randomized controlled trials (RCT), published at any time, which report adverse clinical outcomes, including deep vein thrombosis, pulmonary embolus, and adverse reactions following arthroscopic procedures, in which patients were randomized into an experimental group who received TXA (either intravenously or via intra-articular injection) preoperatively and a control group who did not receive TXA. The exclusion criteria were those studies that were non-RCT and did not assess outcomes following arthroscopic procedures. The studied outcomes included: thromboembolic events, adverse drug reactions, postoperative drain output, VAS pain scores, and joint aspiration requirements.Results:Thirteen prospective randomized controlled trials met inclusion criteria for analysis and were included in this review. These studies examined a total of 1,159 arthroscopic procedures, comprised of 174 hip arthroscopy procedures, 810 knee arthroscopy procedures for ACL reconstruction, 103 knee arthroscopy procedures for meniscectomy or repair, and 72 shoulder arthroscopy procedures for rotator cuff repair. Tranexamic acid use in arthroscopic procedures resulted in no increase in thromboembolic events or adverse drug reactions, with no thromboembolic events or adverse drug reactions reported across the 1,159 procedures. Tranexamic acid in IV and IA forms used in ACL reconstruction reduced 24-hour postoperative drain output (-48.47cc; P=0.001 in IV TXA and -39.11cc, P=0.004 in IA TXA group when compared to control) and improved VAS pain scores in the early postoperative period at 1 week (-1.4, P<0.00001 in IV TXA and -1.68, P<0.00001 in IA TXA when compared to control) as demonstrated in Figure 1a and 1b. Further, IV TXA resulted in a significant reduction in postoperative aspiration requirement compared to control (Odds Ratio 0.37, P=0.02) following ACL reconstruction as demonstrated in Figure 2.Conclusions:The use of IV or IA TXA in arthroscopic surgery including rotator cuff repair, meniscus, femoroacetabular impingement surgery, and ACL reconstruction is safe and confers no increased risk of thromboembolic events. IV and IA TXA have proven to be effective in reducing postoperative drain output and even reducing pain in the early postoperative period following ACL reconstruction. Finally, IV TXA has been shown to reduce the need for postoperative aspiration following ACL reconstruction.

Current possibilities of pharmacological correction of neuroimmune joint damage in patients with knee osteoarthritis in long COVID conditions

Objective: to evaluate the efficacy and safety of the parenteral form of pharmaceutical chondroitin sulfate (CS) in neuroimmune joint damage in patients with early knee osteoarthritis (OA) in long COVID.Patients and methods. An open prospective controlled randomized study was conducted, its duration was 50 days of active controlled therapy. The study included 82 patients (age 57–63 years, men – 29, women – 53) with clinical symptoms of early knee OA and confirmed long COVID type 2 (persistence of symptoms 4–12 weeks after infection with SARS-CoV2). The diagnosis of OA was established in accordance with the updated classification criteria for early knee OA (2018).Patients were randomized into two groups: group 1 – the main group (n=42) and group 2 – control group (n=40). Patients in both groups received celecoxib at a dose of 200 mg with the possibility of reducing the dose to 100 mg or completely discontinuing the drug if necessary. Patients of the 1st group additionally received a parenteral form of CS (Chondroguard® solution for intramuscular and intraarticular administration, 100 mg/ml). At baseline (Day 1) and on the 50th day of the study, pain intensity was assessed in all patients using a visual analogue scale (VAS), the degree of functional impairment (FI) of the joints according to the Lequesne index, ultrasound of the knee joint was performed, CRP, D-dimer, fibrinogen, interleukin (IL) 1β, IL6 levels were studied. The presence of SARS-CoV2 was determined by polymerase chain reaction in scrapings from the mucous membrane of the nasal cavity and oropharynx, and a qualitative proteomic analysis was performed (1-2DE, MALDI-TOF/TOF-MS, PathCards database). The safety of therapy was assessed using the WHO and Naranjo scales.Results and discussion. It was established that CS therapy was well tolerated and was accompanied by a significant decrease in pain intensity according to VAS (U-test=5.71; p&lt;0.0001), in FI according to the Lequesne scale (U-test=6.32; p&lt;0.0001), in manifestations of synovitis and tendinitis in the group treated with CS and celecoxib, compared with the control group. During the treatment by CS a statistically significant (p&lt;0.0001) decrease in the level of pro-inflammatory markers in the blood serum (CRP, IL6, IL1β), D-dimer and fibrinogen was noted. Proteomic analysis showed a decrease in the blood serum of patients of the 1st group of eotaxin 1, IL8, IL15, interferon γ inducible protein 10 levels, and an increase in the expression of nerve fiber growth factor β, an antagonist of the IL1 receptor.Conclusion. The use of pharmaceutical parenteral CS in combination with oral celecoxib in patients with early OA of the knee joint, the clinical signs of which manifested after infection with SARS-CoV2 and persisted in long COVID conditions, contributed to a decrease in the severity of pain and stiffness in the knee joint, as well as improved functional capabilities.

Nanoscale self-assembling prodrugs of sulfapyridine for treatment of arthritis: Harnessing the dual approach

Rheumatoid arthritis is a chronic, autoimmune, inflammatory joint disease, affecting mainly joints of hands, wrists, and knees. Although a number of potent drugs are available for the treatment of arthritis, the management of this life-long disease becomes challenging because of their poor bioavailability, frequent administration, toxicity, instability and limitations related to their formulation development. Self-assembling nanoparticles are the emerging class of therapeutic drug delivery systems that have been explored in past few years for the treatment of various diseases. Intra-articular administration of these systems prolongs the retention of drug in the target site by virtue of their size as well as two-steps release of the entrapped drugs (disassembly and then lysis of prodrug to release the active drug) and provide a sustained action which is desirable in this condition. Based on the prior reports, it is hypothesized that self-assembly delivery systems of sulfapyridine will provide an effective and sustained treatment of rheumatoid arthritis. Promoieties including saturated, unsaturated fatty acids and amino acids are proposed.

ALPK1 Aggravates TMJOA Cartilage Degradation via NF-κB and ERK1/2 Signaling

Temporomandibular joint osteoarthritis (TMJOA) is a common degenerative joint disease without effective intervention strategies. Previous research implied that alpha-kinase 1 (ALPK1) is involved in the inflammatory responses of gout, a chronic arthritis. Herein, we found the main distribution of ALPK1 in a proliferative layer of condylar cartilage and marrow cavity of subchondral bone, as well as a lining layer of synovial tissues in human temporomandibular joint. Moreover, the expression of ALPK1 was augmented in degraded condylar cartilage of monosodium iodoacetate (MIA)–induced TMJOA mice. After MIA induction, ALPK1 knockout mice exhibited attenuated damage of cartilage and subchondral bone, as well as synovitis, as compared with wide type mice. In contrast, intra-articular administration of recombinant human ALPK1 aggravated the pathology of MIA-induced TMJOA. Furthermore, ex vivo study demonstrated that ALPK1 exacerbated chondrocyte catabolism by upregulating matrix metalloproteinase 13 and cyclooxygenase 2 by activating NF-κB (nuclear factor–kappaB) signaling and suppressed anabolism by downregulating aggrecan by inhibiting ERK1/2 (extracellular signal–regulated kinase 1/2) in articular chondrocytes. Taken together, ALPK1 exacerbates the degradation of condylar cartilage during TMJOA through the NF-κB and ERK1/2 signaling pathway. This study provides a new insight regarding the role of ALPK1 during TMJOA pathology.

Efficacy of a Novel Intra-Articular Administration of Platelet-Rich Plasma One-Week Prior to Hyaluronic Acid versus Platelet-Rich Plasma Alone in Knee Osteoarthritis: A Prospective, Randomized, Double-Blind, Controlled Trial.

Recent studies have suggested that the combined injection of platelet-rich plasma (PRP) and hyaluronic acid (HA) may have additive benefits for knee osteoarthritis over PRP alone, but there is insufficient evidence to support this combined injection. Moreover, the simultaneous injection of PRP and HA may offset the combined effect. Hence, the aim of this prospective, randomized, double-blind study was to assess their combined efficacy with a novel injection protocol. Forty-six study subjects with unilateral knee osteoarthritis were randomized to receive either a single-dose injection of HA (intervention group) or normal saline (control group) 1 week after a single-dose injection of leukocyte-poor PRP. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and static balance and the risk of falls measured by Biodex Balance System were, respectively, the primary and secondary outcome measures. Evaluations were performed at baseline, 1 month, 3 months, 6 months, and 12 months post-injection. The intervention group exhibited significant declines in WOMAC pain, stiffness, and total scores, as well as static balance, compared to the control group (p < 0.05). These randomized double-blind control trials, with novel protocol of intra-articular injection of PRP 1-week prior to HA, provide greater symptom relief and improve static balance compared to PRP alone in patients with knee osteoarthritis.

A Pilot, Open-Label Study to Evaluate the Efficacy of Intra-Articular Administration of a Caninized TNF Receptor Fc Fusion Protein as a Treatment for Osteoarthritis-Associated Joint Pain.

Tumor necrosis factor-α (TNF-α) is a potential target for osteoarthritis (OA) treatment. In several recent clinical studies in human OA, anti-TNF-α therapy showed promising results; however, these were open-label and based on patient-reported outcome measures. In this study, we developed a caninized TNF-α receptor-Fc (caTNFR-Fc) fusion protein and conducted a non-randomized, open-label, pilot study in dogs with OA using objectively measured ground reaction forces and activity. The aims of the study were to assess the efficacy of the intra-articular (IA) injection of the caTNFR-Fc fusion protein as a treatment for OA pain, and additionally to evaluate TNF concentrations in synovial fluid (SF) between joints with/without OA in dogs. Dogs (n = 12) with single-limb lameness due to single joint appendicular OA were recruited. All dogs received caTNFR-Fc fusion protein injection into the affected joint under sedation. Objective kinetic gait analysis using force plate was performed prior to (baseline), and at 14- and 28-days following treatment. Additionally, SF samples were collected from OA joints (n = 69) and non-OA joints (n = 79) in a different cohort of dogs and TNF-α were measured using enzyme-linked immunosorbent assay. No significant treatment effects on the limb use, activity, and the questionnaire were found. The concentration of TNF-α was significantly higher in OA joints than in healthy joints (p = 0.0019), but TNF-α was detected in only 10/69 OA samples. The IA injection of caTNFR-Fc fusion protein provided no benefit in terms of objective limb use and activity data in dogs with OA in this pilot study. Although the SF concentration of TNF-α was significantly higher in OA joints, few OA joints had measurable TNF-α. Collectively, the data indicate TNF-α may not be a good therapeutic target in canine OA.