Intra-articular Research Articles

A phase 2, open-label, adaptive, dose-ranging study with long-term extension to evaluate the safety, tolerability, efficacy, and pharmacokinetics of intra-articular AMB-05X injections in patients with tenosynovial giant cell tumor.

TPS11585 Background: CSF1R is a clinically validated target for Tenosynovial Giant Cell Tumor (TGCT). CSF1 is overexpressed in TGCT and, via action at the colony-stimulating factor 1 receptor (CSF1R), leads to the proliferation of synovial-like mononuclear cells and recruitment of multinucleate giant cells, foam cells, siderophages, and inflammatory cells, which compose the bulk of the neoplasm. Although nonmetastatic in nature, TGCT can develop into locally destructive lesions that cause significant local tissue injury, loss of joint function, and impaired quality of life. When complete resection is achievable without significant morbidity, the standard of care for patients with TGCT is surgical resection. Recurrence after surgery occurs in up to 30% of patients with localized TGCT and 83% of patients with diffuse TGCT ( Mastboom 2019, Patel 2017). Repeat surgeries may be necessary but often leads to further morbidity, complications, and reduced function of affected joints. A safe, effective, and convenient pharmacotherapy is a desirable addition to the therapeutic armamentarium for TGCT. AMB-05X is a potent and selective anti-CSF1R monoclonal antibody in development for local treatment of TGCT. Intra-articular (IA) injection of AMB-05X enables high drug concentration at the tumor site while minimizing systemic exposure and toxicity. A proof-of-concept study of IA AMB-05X for TGCT found clinically meaningful improvement in objective response rate, functional (pain, stiffness, range of motion) and quality of life measures after 12 weeks of therapy with no serious and a low number of adverse events associated with targeting CSF1R. This phase 2 study aims to establish the optimal dosing regimen and local administration of AMB-05X and confirm the efficacy and safety of 24 weeks and longer treatment. Methods: AMB-051-07 (NCT05349643) is an open-label, multicenter, phase 2 study of AMB-05X in patients with TGCT. The trial is being conducted at multiple sites in North America, Europe, and Australia. The dosing schedule includes an injection interval of every 4 weeks and longer, including an extended dosing period. Adult patients with histologically confirmed symptomatic TGCT with one joint involvement whether surgically amenable or non-amenable with measurable disease and adequate organ function are being enrolled. After the initial cohort of patients with TGCT of the knee, other joints may be enrolled pending evaluation by the DMC. The primary study outcome measures are objective response rate (ORR) per RECIST v1.1 by central radiology review and safety. Secondary outcome measures include ORR per modified RECIST and Tumor Volume Score, duration of response, time to response, PRO/QOL (including range of motion, stiffness, pain), pharmacodynamics and pharmacokinetics. Clinical trial information: NCT05349643 .

Comparing the Efficacy of Intra-articular Platelet-Rich Plasma and Corticosteroid Injections in the Management of Frozen Shoulder: A Randomized Controlled Trial.

Introduction Periarthritis of the shoulder, or frozen shoulder (FS), is a common, painful, and disabling condition with varied treatment strategies. Intra-articular (IA) corticosteroid (CS) injections are a popular treatment option, but their efficacy is often temporary. Platelet-rich plasma (PRP) has emerged as an alternative therapy for adhesive capsulitis, but the literature on its effectiveness is limited. This study aimed to compare the efficacy of IA PRP and CS injections in managing FS. Methods In this prospective, randomized study, 68 patients who met the inclusion criteria were enrolled and randomized using a computer-generated table into two groups: Group 1 (IA PRP) received 4 ml PRP, and Group 2 (IA CS) received 2 ml (80 mg) of methylprednisolone acetate mixed with 2 ml normal saline (for a total of 4 ml) as a CS injection in the IA area of the shoulder. Outcome measures included pain; shoulder range of motion (ROM); the condensed version of the disabling conditions of the arm, shoulder, and hand (QuickDASH) score; and the shoulder pain and disability index (SPADI) score. Participants were monitored via follow-up for 24 weeks, with pain and function assessed at each evaluation using the visual analog scale (VAS) score, the SPADI score, and the QuickDASH score. Results The IA PRP injections demonstrated better long-term outcomes than the IA CS injections, significantly improving pain, shoulder ROM, and daily activity performance. After 24 weeks, the mean VAS score in the PRP and methylprednisolone acetate groups was 1.00 (1.0 to 1.0) and 2.00 (2.0 to 2.0), respectively (P≤0.001). The mean QuickDASH score was 41.83 ± 6.33 in the PRP group and 48.76 ± 5.08 in the methylprednisolone acetate group (P≤0.001). The mean SPADI score was 53.32 ± 7.49 in the PRP group and 59.24 ± 5.80 in the methylprednisolone acetate group (P≤0.001), indicating a significant improvement in the PRP group's pain and disability scores after 24 weeks. The rate of complications was similar between the two groups. Conclusions Our findings suggest that IA PRP injections provide better long-term results than IA CS injections for managing FS. Platelet-rich plasma can be used as a treatment modality for better outcomes, particularly when the patient is contraindicated or refuses CS treatment. Further research is needed to evaluate the efficacy of these treatment modalities at different stages of FS and explore the potential benefits of ultrasound-guided injections.

Patient characteristics cannot predict the long-term effect of an intra-articular bupivacaine and corticosteroid injection in patients with femoroacetabular impingement: A retrospective cohort study

BackgroundTo evaluate predictors for effect of an intra-articular (IA) bupivacaine and corticosteroid injection in patients with femoroacetabular impingement syndrome (FAIS). MethodsAll patients between 18 and 50 years old with FAIS who received an intra-articular (IA) bupivacaine and corticosteroid injection between 2016 and 2019 were eligible for this retrospective study. Two groups were made, the non-arthroscopy group (patients for whom conservative treatment with physiotherapy and an IA bupivacaine and corticosteroid injection was sufficient) and the arthroscopy group (patients who needed an arthroscopy because conservative treatment and an IA bupivacaine and corticosteroid injection failed). Multiple regression analysis was performed to analyse the effect of the IA corticosteroid injection and to predict arthroscopic intervention based on sex, age, body mass index, duration of complaints, alpha angle and abnormal bone morphology. ResultsIn total 103 patients were included; 46 in the arthroscopy group and 57 in the non-arthroscopy group. The groups had similar baseline characteristics. A total of 37 (36%) patients had an effect of 3 months or longer from the IA corticosteroid injection; 31 (54%) were patients in the non-arthroscopy group versus 6 (13%) patients in the arthroscopy group (P < 0.001). Male sex seems to have an negative influence on the duration of the effect of the injection. None of the variables could significantly predict if a patient would undergo arthroscopic intervention (F(7,103) = 8.54, p = 0.3, R2 = 0.11). The effect of the IA injection could not be predicted (p = 0.1; R2 = 0.13). ConclusionThere are no patient characteristics that predict who would and who would not benefit from the IA bupivacaine and corticosteroid injection in patients with FAIS and who would need an arthroscopic intervention within 1 year after the injection. Only male sex seems to have an negative influence on the duration of the effect of the injection.

Derivation of a clinical decision rule for a bone marrow aspirate concentrate injection in knee osteoarthritis.

Aim: To develop a simple clinical decision rule (CDR) to identify people with knee osteoarthritis who are likely or unlikely to benefit from bone marrow aspirate concentrate (BMAC) injection. Materials & methods: A total of 92 people with clinical and radiographic evidence of refractory knee osteoarthritis received a single intra-articular (IA) BMAC injection. Multiple logistic regression analysis was used to determine which combination of risk factors predicted BMAC responsiveness. A responder was defined as a person whose knee pain improved more than 15% from baseline 6months postprocedure. Results: The CDR demonstrated that those with lower pain levels, or high pain levels with previous surgery, could be predicted to benefit from a single IA BMAC injection. Conclusion: A simple CDR containing three variables predicted responsiveness to a single IA knee BMAC injection with high accuracy. Further validation of the CDR is required prior to routine use in clinical practice.

An injectable copolymer of fatty acids (ARA 3000 BETA) as a promising treatment for osteoarthritis

Osteoarthritis (OA) is the most prevalent rheumatic disease and a fast growing cause of disability. Current pharmacological treatments include antalgics and non-steroid anti-inflammatory drugs to control pain and inflammation as well as slow acting drugs such as intra-articular (IA) administration of hyaluronic acid. Oral supplementation or diet rich in polyunsaturated free fatty acids are proposed but evidence for benefit is still under debate. We here investigated the therapeutic potential of ARA 3000 BETA, an injectable copolymer of fatty acids, at the structural level in OA. Collagenase-induced osteoarthritis model was induced in C57BL/6 mice by collagenase injection into knee joint. Mice were treated with one or two IA or four intra-muscular injections (IM) of ARA 3000 BETA. At sacrifice, knee joints were recovered for cartilage analysis by confocal laser scanning microscopy (CLSM) and bone analysis by micro-computed tomography system. OA histological scoring was performed after safranin O/fast green staining. Histological analysis revealed a protective effect against cartilage degradation in treated knee joints after IM and IA administration. This was confirmed by CLSM with a significant improvement of all articular cartilage parameters, including thickness, volume and surface degradation whatever the administration route. A slight protective effect was also noticed on subchondral bone parameters and knee joint calcification after IM administration and to a lesser extent, two IA injections. We demonstrated the therapeutic efficacy of injectable ARA 3000 BETA in OA with a protection against cartilage and bone alterations providing the proof-of-concept that clinical translation might be envisioned to delay disease progression.

Intra-Articular Injections for Pain Relief Following Knee Arthroscopy: A Literature Review

Arthroscopy procedures for the knee are excellent and tend to be outpatient procedures. Pain control after arthroscopic surgery is an important aspect of patient satisfaction and quicker return to daily activities following surgery. The objective of this article was to review the current literature regarding pain management after knee arthroscopy using intra-articular (IA) injections. Our goal in this article is to review the drugs that have been suggested in various articles for IA injections following knee arthroscopy to control pain. In conclusion, the current evidence suggests that combining IA lidocaine and morphine with tranexamic acid (TXA), in addition to ketorolac, is effective for pain relief after arthroscopic knee surgery.

Targeting damaged collagen for intra-articular delivery of therapeutics using collagen hybridizing peptides.

The objective of this study was to investigate the potential of collagen hybridizing peptides (CHPs), which bind to denatured collagen, to extend the retention time of near-infrared fluorophores (NIRF) following intra-articular (IA) injection in rat knee joints. CHPs were synthesized with a NIRF conjugated to the N-terminus. Male Sprague-Dawley rats were assigned to one of four experimental groups: healthy, CHP; osteoarthritis (OA), CHP; healthy, scrambled-sequence CHP (sCHP), which has no collagen binding affinity; or OA, sCHP. Animals in the OA groups received an IA injection of monosodium iodoacetate to induce OA. All animals then received the corresponding CHP injection. Animals were imaged repeatedly over 2 weeks using an in vivo fluorescence imaging system. Joint components were isolated and imaged to determine CHP binding distribution. Safranin-O and Fast Green histological staining was performed to confirm the development of OA. CHPs were found to be retained within the joint following IA injection in both healthy and OA animals for the full study period. In contrast, sCHP signal was negligible by 24-48 h. CHP signal was significantly greater (p < 0.05) in OA joints when compared to healthy joints. At the 2-week end point, multiple joint components retained CHPs, including cartilage, meniscus, and synovium. CHPs dramatically extended the retention time of NIRFs following IA injection in healthy and OA knee joints by binding to multiple collagenous tissues in the joint. These results support the pursuit of further research to develop CHP based therapeutics for IA treatment of OA.

The influence of the COVID-19 pandemic, sex, and age on temporomandibular disorders subtypes in East Asian patients: a retrospective observational study

BackgroundDespite its major existential, societal, and health impacts, research concerning the COVID-19 pandemic and Temporomandibular disorders (TMDs) is still limited. This study examined the effect of the pandemic on TMD subtypes and elucidated the influence of the pandemic, sex, and age on the prospect of pain-related (PT) and/or intra-articular (IT) TMDs in East Asian patients.MethodsData were accrued from consecutive new patients attending two university-based TMD/orofacial pain clinics in China and South Korea, 12 months before (BC; Mar 2019-Feb 2020) and during (DC; Mar 2020-Feb 2021) the COVID-19 pandemic. TMD diagnoses were derived from pertinent symptoms, signs, and radiographic findings according to the Diagnostic Criteria for TMDs (DC/TMD) methodology. Patients were subsequently categorized into those with PT, IT, and combined TMDs (CT) and also stratified by attendance period, sex, and age groups (adolescents/young adults [AY] and middle-aged/older adults [MO]) for statistical analyses using Chi-square/Mann-Whitney U tests and logistic regression analyses (α = 0.05).ResultsThe BC and DC groups comprised 367 (75.2% females; 82.8% AY) and 471 (74.3% females; 78.3% AY) patients correspondingly. No significant differences in sex and age group distributions were observed. The DC group had significantly more PT/IT conditions with higher prevalence of myalgia, headache, and degenerative joint disease than the BC group. Univariate analyses showed that PT/CT was associated with sex and age, whereas IT was related to the pandemic and age. However, multivariate analyses indicated that the odds of PT were affected by sex (OR = 2.52) and age (OR = 1.04) while the odds of IT (OR = 0.95) and CT (OR = 1.02) were influenced by age only.ConclusionsThe COVID-19 pandemic, as an impact event, did not influence the prospect of PT and/or IT. Sex and age appeared to play more crucial roles in the development of PT and IT/CT respectively.

P074 Intra-articular platelet-rich plasma injections versus intra-articular corticosteroid injections for the symptomatic management of knee osteoarthritis: a systematic review and meta-analysis

Abstract Background/Aims Osteoarthritis (OA) is the commonest reason for orthopaedic referral in the UK, with the burden of knee OA affecting 10-25% of patients over 60 and 6% of those over 30. Intra-articular (IA) corticosteroid (CS) injections are the mainstay of treatment for symptomatic management in knee OA, particularly in the UK. IA platelet-rich-plasma (PRP) injections are a promising alternative, but no systematic reviews to date have compared them to the current standard of care, IA CS injections. We aim to investigate the effect of IA PRP injections versus IA corticosteroid injections for the symptomatic management of knee OA. Methods All published trials comparing IA PRP and CS injections for knee OA were included. MEDLINE, EMBASE, Scopus and Web of Science were searched through June 2020. Risk of bias was assessed using the Cochrane Risk of Bias tool and overall was deemed low. A random effects model was used to calculate standardized mean difference with 95% confidence interval in WOMAC, VAS and KOOS scores (or subscores), comparing IA PRP to CS injections across studies at different time points of follow-up. Where studies used different outcome measures, these were combined using the standardised mean difference (SMD). Results 8 studies and 648 patients were included. 443 (68%) were female, mean age 59 years, with a mean BMI of 28.4. OA was diagnosed radiologically using the Kellgren-Lawrence scale. Compared with CS injections, PRP was significantly better in reducing OA symptoms (pain, stiffness, functionality) at 3-, 6- and 9-months post-intervention (P &amp;lt; 0.01). The greatest effect was observed at 6 and 9 months (-0.78 (-1.34 to -0.23) SD and -1.63 (-2.14 to -1.12) SD respectively). At 6 months, this equates to an additional reduction of 9.51 in WOMAC or 0.97 on the VAS pain scales. On WOMAC pain and stiffness subscales, there were significant additional reductions in the PRP group for pain and stiffness (-2.66 (-4.73 to -0.60), P &amp;lt; 0.01 and 1.95 (-2.30 to -1.59), P &amp;lt; 0.01 respectively), but not functionality at 6 months. At 6 months PRP allowed greater return to sporting activities than CS injections, as measured by the KOOS subscale for sporting activity, of magnitude 9.7 (-0.45 to 19.85) (P = 0.06). Triple injections of PRP, generally separated by a week, were superior to single injections over 12 months of follow-up (P &amp;lt; 0.001). Considerable heterogeneity in the preparation of PRP was observed. Conclusion IA-PRP injections produce superior outcomes when compared with CS injections for symptomatic management of knee OA, including improved pain management, less joint stiffness and better participation in exercise/sporting activity at 12 months follow-up. Giving three IA-PRP, with injections separated by a week, appears more effective than one IA-PRP injection. IA corticosteroid injections should no longer be routinely used for symptomatic management of knee OA. Disclosure M.E.D. McLarnon: None. N. Heron: None.

Notch signaling is activated in knee-innervating dorsal root ganglia in experimental models of osteoarthritis joint pain

BackgroundWe aimed to explore activation of the Notch signaling pathway in knee-innervating lumbar dorsal root ganglia (DRG) in the course of experimental osteoarthritis (OA) in mice, and its role in knee hyperalgesia.MethodsCultured DRG cells were stimulated with the TLR4 agonist, lipopolysaccharide (LPS). Notch signaling in the cells was either inhibited with the γ-secretase inhibitor, DAPT, or with soluble Jagged1, or activated through immobilized Jagged1. CCL2 production was analyzed at mRNA and protein levels. In in vivo experiments, knee hyperalgesia was induced in naïve mice through intra-articular (IA) injection of LPS. The effect of inhibiting Notch signaling was examined by pre-injecting DAPT one hour before LPS. OA was induced through surgical destabilization of the medial meniscus (DMM) in male C57BL/6 mice. Gene expression in DRG was analyzed by qRT-PCR and RNAscope in situ hybridization. Activated Notch protein (NICD) expression in DRG was evaluated by ELISA and immunofluorescence staining. DAPT was injected IA 12 weeks post DMM to inhibit Notch signaling, followed by assessing knee hyperalgesia and CCL2 expression in the DRG.ResultsIn DRG cell cultures, LPS increased NICD in neuronal cells. Inhibition of Notch signaling with either DAPT or soluble Jagged1 attenuated LPS-induced increases of Ccl2 mRNA and CCL2 protein. Conversely, activating Notch signaling with immobilized Jagged1 enhanced these LPS effects. In vivo, IA injection of LPS increased expression of Notch genes and NICD in the DRG. Pre-injection of DAPT prior to LPS alleviated LPS-induced knee hyperalgesia, and decreased LPS-induced CCL2 expression in the DRG. Notch signaling genes were differentially expressed in the DRG from late-stage experimental OA. Notch1, Hes1, and NICD were increased in the neuronal cell bodies in DRG after DMM surgery. IA administration of DAPT alleviated knee hyperalgesia post DMM, and decreased CCL2 expression in the DRG.ConclusionsThese findings suggest a synergistic effect of Notch signaling with TLR4 in promoting CCL2 production and mediating knee hyperalgesia. Notch signaling is activated in knee-innervating lumbar DRG in mice with experimental OA, and is involved in mediating knee hyperalgesia. The pathway may therefore be explored as a target for alleviating OA pain.

The OA Trial Bank: Update of individual patient data meta-analysis of intra-articular glucocorticoids in persons with knee and hip osteoarthritis

ObjectiveTo evaluate the efficacy of intra--articular (IA) glucocorticoid for knee or hip osteoarthritis (OA) in specific subgroups of patients according to the baseline severity of pain and inflammatory signs using individual patient data (IPD) from existing trials. Furthermore, this study aims to assess if a baseline pain cut-off was associated with clinically important effectiveness of IA glucocorticoid. This is an update of an IA glucocorticoid IPD meta-analysis by the OA Trial Bank. MethodRandomized trials evaluating one or more IA glucocorticoid preparations in hip and knee OA, published to May 2018 were selected. IPD of patient and disease characteristics and outcome measures were acquired. The primary outcome was pain severity at short-term follow-up (up to 4 weeks). Potential interaction effect of severe pain (≥70 points, 0–100 scale) and signs of inflammation at baseline were studied using a two-stage approach with general liner model followed by random effects model. Analysis of trend was conducted, assessing if a baseline pain cut-off was associated with the threshold for clinically important treatment effect of IA glucocorticoid compared to placebo. ResultsFour out of 16 eligible randomized clinical trials (n ​= ​641) were combined with the existing OA Trial Bank studies (n ​= ​620), yielding 1261 participants from eleven studies. Participants with severe baseline pain compared to those with less severe pain had greater pain reduction at mid-term (around 12 weeks) (mean reduction: −6.90 (95%CI -10.91; −2.90)), but not at short- and long-term. No interaction effects were found between inflammatory signs and IA glucocorticoid injections compared to placebo at all follow-up time-points. Analysis of trend demonstrated treatment response to IA glucocorticoid from baseline pain levels >50 (0–100 scale) and above. ConclusionThis updated IPD meta-analysis demonstrated that participants with severe pain compared to those with less severe pain at baseline experienced significantly more pain relief with IA glucocorticoid compared with placebo at mid-term.

Comparison of Blood Loss with the Use of Intravenous and Intraarticular Tranexamic Acid Versus Isolated Intraarticular in Primary Knee Arthroplasty.

Objective The objective of this work is to compare blood loss during primary knee arthroplasty with the use of intravenous and intraarticular (IV + IA) tranexamic acid versus intraarticular (IA) tranexamic acid alone. Methods This is a randomized, double-blind clinical trial. Patients with indication for primary total knee arthroplasty were recruited in a specialized clinic, where they were operated by the same surgeon, always using the same surgical technique. Thirty patients were allocated in the IV + IA tranexamic acid group and 30 patients in the IA tranexamic acid group, according to randomization. Blood loss was compared through hemoglobin, hematocrit, drain volume, and blood loss estimation (Gross and Nadler calculus). Results After collection, data from 40 patients were analyzed, 22 in the IA group and 18 in the IV + IA group. There were 20 losses due to collection error. Between groups IA and IV + IA, there were no significant differences in 24 hours between hemoglobin levels (10.56 vs. 10.65 g/dL; F 1.39 = 0.63, p = 0.429), erythrocyte (3.63 vs. 3.73 million/mm 3 ; F 1.39 = 0.90, p = 0.346); hematocrit (32.14 vs. 32.60%; F 1.39 = 1.39, p = 0.240); drainage volume (197.0 vs. 173.6 mL; F 1.39 = 3.38 p = 0.069); and estimated blood loss (1,002.5 vs. 980.1; F 1.39 = 0.09, p = 0.770). The same occurred in comparisons conducted after 48 hours postoperatively. Time was a significant factor for the change of all outcome variables. However, the treatment did not modify the effect of time on these outcomes. No individual presented any thromboembolic event during the work period. Conclusions The use of IV + IA tranexamic acid showed no advantage in reducing blood loss when compared to the use of IA tranexamic acid alone in primary knee arthroplasties. This technique proved to be safe, since no thromboembolic event occurred during the development of the work.

Quantitative PET tracking of intra-articularly administered 89Zr-peptide-decorated nanoemulsions.

Intra-articular (IA) administration of drugs for the treatment of diseases such as rheumatoid arthritis, osteoarthritis and psoriatic arthritis is a common strategy; however, the rapid clearance from the synovial fluid restricts their effectivity due to the limited retention time. Drug Delivery Systems (DDS) are currently being developed to increase their joint retention time. This study compares the biodistribution and retention time of a senolytic peptide (PEP), with potential application in osteoarthritis disease, and this senolytic peptide encapsulated in a DDS based on a lipid nanoemulsion (PEPNE) by using positron emission tomography (PET) imaging. To this aim, the PEP was conjugated with a chelating agent (DFO) and radiolabeled with zirconium-89 (89Zr). Then, [89Zr]-PEP was encapsulated in a novel nanoemulsion formulation, composed by vitamin E, sphingomyelin, and a lipid-PEG. Afterward, healthy rats were administered with either the [89Zr]-PEP or the [89Zr]-PEP-NE via IA injection and underwent PET scans at 0.5-, 24-, 48-, 72-, 168-, 240- and 336h post-injection. To assess the biodistribution of both radiotracers, several volume-of-interest were manually drawn in different organs of the rat body and the %ID/organ was calculated. The [89Zr]-PEP was successfully encapsulated in the NE and their physicochemical properties were minimally affected by the radiolabeling buffer. Adequate stability of both [89Zr]-PEP and [89Zr]-PEP-NE was found in synovial fluid over 72h. Quantitative data from PET images revealed a significantly higher [89Zr]-PEP-NE retention in the injected knee than with [89Zr]-PEP in all follow-up PET scans. The [89Zr]-PEP %ID/organ values in the liver and kidney were significantly higher than those from [89Zr]-PEP-NE, which might indicate a faster elimination of the [89Zr]-PEP. Therefore, the study highlights the higher retention time on the target site of the [89Zr]-PEP-NE which may improve the therapeutic effects of the peptide. Thereby, the novel nanoemulsion formulation seems to be a successful DDS for IA injection. In addition, these results represent the first study that evaluates the distribution of a PET-guided DDS after its IA administration.

A comparative study of the efficacy of intra-articular injection of different drugs in the treatment of mild to moderate knee osteoarthritis: A network meta-analysis.

Knee osteoarthritis (KOA) has a high clinical prevalence and frequently interferes with patients normal lives. In KOA patients, evidence suggests that intra-articular (IA) injection improves joint function and decreases discomfort. Several IA injection treatments are used in daily practice to improve symptomatic control of knee osteoarthritis, but their efficacy is frequently disputed. This network meta-analysis compares the efficacy of different IA injections for mild to moderate knee osteoarthritis. Seven databases (PubMed, EMBASE, Web of Science, Cochrane Library, China Biology Medicine disc, WanFang, and China National Knowledge Infrastructure) were searched for randomized controlled trials published up to and including December 20, 2021, and final follow up indicators were used. Visual analogue scale (VAS) score and The Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index (WOMAC) score change from baseline were the primary outcomes. We used the Cochrane risk of bias tool to assess the quality and risks of biases of papers. We calculated the weighted mean difference (WMD) and 95% confidence interval (CI) for each outcome. State (Version 15.1, Texas, USA) and SPSS (Version 20, Chicago, USA) was used in all statistical analyses, and Review Manager (version 5.4) was used in assessing the risks of biases. Our study included 16 randomized controlled trials with a total of 1652 patients. platelet-rich plasma (PRP) IA injection therapy had the highest likelihood of being the best intervention in reducing WOMAC pain (surface under the cumulative ranking area [SUCRA] 84.7%), stiffness (SUCRA 95.1%), and function (SUCRA 98.5%) scores, according to the SUCRA. The best measures for lowering the WOMAC total and VAS scores were IA injection platelet-rich plasma-derived growth factor (SUCRA 84.9%) and hyaluronic acid and platelet-rich plasma (SUCRA 84.9%). In the VAS score group, PRP outperformed hyaluronic acid (HA) (WMD 1.3, 95% CI 0.55-2.55) and corticosteroids (CS) (WMD 4.85, 95% CI 4.02-5.08), according to the forest map results. PRP also outperformed CS (WMD 14.76, 95% CI 12.11-17.41), ozone (WMD 9.16, 95% CI 6.89-11.43), and PRP + HA (WMD 2.18, 95% CI 0.55-3.81) in the WOMAC total score group. Furthermore, PRP outperforms other drugs in terms of reducing WOMAC function, stiffness, and function score. In patients with mild to moderate KOA, IA injection PRP outperformed IA injection ozone, HA, CS, platelet-rich plasma-derived growth factor, and hyaluronic acid and platelet-rich plasma in terms of pain, stiffness, and dysfunction.

Intra-articular Injection of a B Cell Depletion Antibody Enhances Local Exposure to the Joint-Draining Lymph Node in Mice with Collagen-Induced Arthritis.

Changes to the number, type, and function of immune cells within the joint-draining lymphatics is a major contributor to the progression of inflammatory arthritis. In particular, there is a significant expansion in pathogenic B cells in the joint-draining lymph node (jdLN). These B cells appear to clog the lymphatic sinuses in the lymph node, inhibit lymph flow, and therefore, reduce the clearance of inflammatory fluid and cells from the joint. Taken together, there is potential to treat inflammatory arthritis more effectively, as well as reduce off-target side effects, with localized delivery of B-cell depleting therapies to the jdLNs. We recently reported that joint-draining lymphatic exposure of biologic disease-modifying anti-rheumatic drugs (DMARDs), including the B cell depletion antibody rituximab, is increased in healthy rats following intra-articular (IA) compared to subcutaneous (SC) or intravenous (IV) administration. This suggests that IA administration of B cell depleting antibodies may increase delivery to target cells in the jdLN and increase the effectiveness of B cell depletion compared to standard SC or IV administration. However, whether enhanced local delivery of DMARDs to the jdLN is also achieved after IA injection in the setting of inflammatory arthritis, where there is inflammation in the joint and jdLN B cell expansion is unknown. We, therefore, assessed the lymph node distribution, absorption and plasma pharmacokinetics, and B cell depletion at different sites after IA, SC, or IV administration of a fluorescently labeled mouse anti-CD20 B cell depleting antibody (Cy5-αCD20) in healthy mice compared to mice with collagen-induced arthritis (CIA). The absorption and plasma pharmacokinetics of Cy5-αCD20 appeared unaltered in mice with CIA whereas distribution of Cy5-αCD20 to the jdLNs was generally increased in mice with CIA, regardless of the route of administration. However, IA administration led to greater and more specific exposure to the jdLNs. Consistent with increased Cy5-αCD20 in the jdLNs of CIA compared to healthy mice, there was a greater reduction in jdLN weight and a trend toward greater jdLN B cell depletion at 24 h compared to 4 h after IA compared to SC and IV administration. Taken together, this data supports the potential to improve local efficacy of B cell depletion therapies through a jdLN-directed approach which will enable a reduction in dose and systemic toxicities.

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis.

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (Treg ) and suppression of Treg destabilization. Sustained release poly-(lactic-co-glycolic) acid (PLGA)-based biodegradable microparticles encapsulating ATRA (PLGA-ATRA MP) are retained in arthritic mouse joints after intra-articular (IA) injection. IA PLGA-ATRA MP enhance migratory Treg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of Treg . PLGA-ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen-induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA-ATRA MP is not associated with generalized immune suppression. PLGA-ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.

The Optimal Dose, Efficacy and Safety of Tranexamic Acid and Epsilon-Aminocaproic Acid to Reduce Bleeding in TKA: A Systematic Review and Bayesian Network Meta-analysis.

The optimal dose and efficacy of tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in total knee arthroplasty (TKA) were under controversial, and we aimed to make comparisons between different doses of TXA and EACA in intravenous (IV) or intra-articular (IA) applications in patients undergoing TKA. This network meta-analysis was guided by the Priority Reporting Initiative for Systematic Assessment and Meta-Analysis (PRISMA). According to the administrations of antifibrinolytic agents, patients in eligible studies were divided into three subgroups: (i) IA applications of TXA and EACA; (ii) IV applications (g) of TXA and EACA; (iii) IV applications (mg/kg) of TXA and EACA. Total blood loss (TBL), hemoglobin (HB) drops and transfusion rates were the primary outcomes, while drainage volume, pulmonary embolism (PE) or deep vein thrombosis (DVT) risk were the secondary outcomes. A multivariate Bayesian random-effects model was adopted in the network analysis. A total of 38 eligible trials with different regimens were assessed. Overall inconsistency and heterogeneity were acceptable. Taking all primary outcomes into account, 1.0-3.0 g TXA were most effective in IA applications, 1-6 g TXA and 10-14 g EACA were most effective in IV applications (g), while 30 mg/kg TXA and 150 mg/kg EACA were most effective in IV applications (mg/kg). None of the regimens showed increasing risk for pulmonary embolism (PE) or deep vein thrombosis (DVT) compared with placebo. 0 g IA TXA, 1.0 g IV TXA or 10.0 g IV EACA, as well as 30 mg/kg IV TXA or 150 mg/kg IV EACA were most effective and enough to control bleeding for patients after TKA. TXA was at least 5 times more potent than EACA.

One-stage revision using intra-articular carbapenem infusion effectively treats chronic periprosthetic joint infection caused by Gram-negative organisms.

Gram-negative periprosthetic joint infection (PJI) has been poorly studied despite its rapidly increasing incidence. Treatment with one-stage revision using intra-articular (IA) infusion of antibiotics may offer a reasonable alternative with a distinct advantage of providing a means of delivering the drug in high concentrations. Carbapenems are regarded as the last line of defense against severe Gram-negative or polymicrobial infection. This study presents the results of one-stage revision using intra-articular carbapenem infusion for treating Gram-negative PJI, and analyzes the characteristics of bacteria distribution and drug sensitivity. We retrospectively reviewed 32 patients (22 hips and 11 knees) who underwent single-stage revision combined with IA carbapenem infusion between November 2013 and March 2020. The IA and intravenous (IV) carbapenem infusions were administered for a single Gram-negative infection, and IV vancomycin combined with IA carbapenems and vancomycin was applied for polymicrobial infection including Gram-negative bacteria. The bacterial community distribution, drug sensitivity, infection control rate, functional recovery, and complications were evaluated. Reinfection or death caused by PJI was regarded as a treatment failure. Gram-negative PJI was mainly caused by Escherichia coli (8/34), Enterobacter cloacae (7/34), and Klebsiella pneumoniae (5/34). Seven cases (7/32) involved polymicrobial PJIs. The resistance rates of penicillin, cephalosporin, quinolones, and sulfonamides were > 10%, and all penicillin and partial cephalosporins (first and second generation) were > 30%. Of 32 cases, treatment failed to eradicate infection in only three cases (9.4%), at a mean follow-up of 55.1 months (SD 25 to 90). The mean postoperative Harris Hip Score and Hospital for Special Surgery knee score at the most recent follow-up were 81 (62 to 91) and 79 (56 to 89), respectively. One patient developed a fistula, and another presented with a local rash on an infected joint. The use of IA carbapenem delivered alongside one-stage revision effectively controlled Gram-negative infection and obtained acceptable clinical outcomes with few complications. Notably, first- and second-generation cephalosporins and penicillin should be administrated with caution, due to a high incidence of resistance.

Formulation of a dual drug-loaded nanoparticulate co-delivery hydrogel system and its validation in rheumatoid arthritis animal model

Rheumatoid arthritis (RA), a systemic autoimmune disease that dramatically affects patients’ quality of life. Given the intricacy of RA’s pathophysiology, no single treatment can completely halt the disease progression. Here, we attempted to treat RA holistically and synergistically by co-delivering methotrexate (MTX), a standard slow-acting anti-rheumatic drug, and phenethyl isothiocyanate (PEITC), a bioactive phytochemical, using a sodium alginate (SA)-pluronic F127 (PF-127) in situ hydrogel formulation. Therefore, in the current study, the co-delivery of MTX and PEITC in the nanoparticulate form could help enhance stability and solubility and facilitate greater penetration in the target arthritic tissues. The fabricated MTX NP and PEITC NE were found to have a minimum particle size, PDI, and good zeta potential. Results from in vitro release studies showed that MTX and PEITC were simultaneously released from the DD NP HG matrix over 6–7 days through diffusion and erosion mechanisms. An intra-articular (IA) injection of DD NP HG dramatically reduced chronic inflammation in adjuvant-induced arthritis (AIA) rats, delayed the onset of bone erosion, significantly reduced synovitis, and down-regulated the inflammatory cytokine expression. Most notably, the co-delivery strategy almost entirely restored the morphological features of the ankle joints of RA rats. The hepatic and renal function tests indicated good biological safety for DD NP HG in RA conditions. Taken together, these findings indicated that DD NP HG could achieve good anti-inflammatory activity and reverse cartilage disruption through a synergistic effect between two nanoparticulate forms of MTX and PEITC, which can effectively improve the drawbacks of their free forms.

Pharmacokinetics of intra-articular buprenorphine in horses with lipopolysaccharide-induced synovitis.

The objective of this study was to describe the pharmacokinetics of intra-articular (IA) administered buprenorphine in horses with lipopolysaccharide (LPS)-induced synovitis. Radiocarpal synovitis was induced in six healthy adult horses with the IA injection of LPS (0.5ng/joint) on two occasions in a randomized cross-over design. Treatments (IA buprenorphine (IAB) at 5μg/kg plus intravenous saline; and intravenous buprenorphine (IVB) at 5μg/kg plus IA saline) were administered 4h following LPS injection. Concentrations of buprenorphine were assessed in plasma and synovial fluid (SF) at 0.5, 2, 6, 12, and 24 h after administration. Pharmacokinetic parameters after IVB and IAB in plasma and synovial fluid were calculated using a nonlinear mixed effects model. IAB was detectable in SF of all horses at 24 h [median concentration of 6.2 (3.46-22.6) ng/mL]. IAB resulted in a median plasma concentration of 0.59 (0.42-1.68) ng/mL at 0.5h and was detectable in all subjects for up to 6 h and in two horses for up to 12 h. IVB resulted in SF concentrations detected up to 6 h in all horses [median concentration of 0.12 (0.07-0.82) ng/mL]. Results suggest that IA buprenorphine remains present in the inflamed joint for at least 24 h and systemic absorption occurs.