Intra-articular Injections Of Hyaluronic Acid Research Articles

Towards reaching consensus on hyaluronic acid efficacy in knee osteoarthritis.

Intra-articular injection of hyaluronic acid (HA) is a controversial treatment for knee osteoarthritis (OA). While clinical efficacy of HA relative to saline injections has been demonstrated in many studies, these results are of limited value in real-world clinical practice since saline injection is not a knee OA treatment. Instead, rigorous postmarket comparative studies of HA versus approved knee OA treatments are encouraged. The conduct of such studies is particularly important given the paucity and heterogeneous nature of current evidence regarding nonsurgical knee OA treatment. KEY POINTS: • Societal guidelines recommend nonsteroidal anti-inflammatory drugs and corticosteroid injections, but not hyaluronic acid injections, for knee osteoarthritis (OA) despite inconsistent supportive data. • This article encourages rigorous comparative post-approval studies to clarify the role of nonsurgical treatments used in clinical practice for knee OA.

Efficacy of local injection therapy with hyaluronic acid of different molecular weight in patients with knee osteoarthritis

Intra-articular administration of hyaluronic acid (HA) is one of the methods of conservative treatment of knee osteoarthritis (OA). However, the data of its efficacy in the modern literature are contradictory.Objective: to assess the efficacy of intra-articular administration of HA preparations with different molecular weight in the treatment of patients with knee OA and to study the factors that can influence the effectiveness of such therapy.Subjects and methods. HA preparations were administered to 60 patients with idiopathic and posttraumatic knee OA. The ratio of women to men was 3:1. The average age was 59.5±13.7 years and body mass index – 30.3±5.8 kg/m2. The presence of enthesitis was evaluated prior to treatment by the characteristic clinical picture. The x-ray stage of OA was determined in accordance with the classification of Kellgren–Lawrence. Distribution of of knee joint lesions, relationship of femur and tibia anatomical axes, presence of varus and valgus deformities were also evaluated. The patients were divided into three groups: 18 patients received low-molecular (LM), 19 – medium-molecular (MM) and 23 – high-molecular (HM) HA. To assess the efficacy of the treatment the severity of pain on a visual analog scale (VAS) and the total score of the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire before, 1, 3 and 6 months after treatment were evaluated.Results and discussion. Enthesitis was detected in 17 (28,3%) patients. Stage I of knee OA was diagnosed in 10 (16.6%), II – in 36 (60%) and III – in 14 (23.3%) patients. Varus deformity was detected in 43 (71.7%) patients, neutral axis of the lower limb - in 14 (23.3%), valgus deformity – in 3 (5%). The most significant decrease in the severity of pain was noted in patients with stage I of knee OA: from 54±17.1 to 10.0±10.0 mm. At stage II, the pain decreased from 59.4±12.6 to 45.5±20.3 mm, and at stage III – from 66.4±13.5 to 60.7±23.3 mm. By the 6th month, the severity of pain in patients with enthesitis was higher, and the values of KOOS total score were worse than in patients without it. At stages II and III of knee OA, the ratio of positive to unsatisfactory results for MM, LM and HM HA was as follows: 2:1, 3:1 and 3.6:1. In the group of patients with excellent results, the value of varus deformation averaged 8.5±1.5°, in patients with a good result – 9.8±2.8°, with a satisfactory result – 11.3±4.5°, and with an unsatisfactory – 11.5±3.2°.Conclusion. Intra-articular injection of HA is very effective at stage I of knee OA. The expression and duration of this effect are reducedwith decrease of cartilage thickness and increase of knee joint varus deformation (i.e., at the II and III stages of knee OA). The presence of varus deformation does not affect HA efficacy. Three factors are important: the appearance of varus deformation of the lower limb with initially neutral axis; the increase of varus deformation; the value of varus deformation >10°.

Effects of Viscosupplementation on Quality of Knee Joint Arthrokinematic Motion Analyzed by Vibroarthrography

To evaluate the influence of viscosupplementation on osteoarthritic knee arthrokinematics analyzed by VAG. It is considered that intra-articular hyaluronic acid injection may improve the function of synovial joints by recovery of friction-reducing properties of articular environment. Thirty-five patients with knee osteoarthritis (grade II according to the Kellgren-Lawrence system) and 50 asymptomatic subjects were enrolled in the study. Patients were analyzed at 3 time points: 1 day before and 2 weeks and 4 weeks after single injection of 1.5% cross-linked hyaluronate. Control subjects were tested once. The vibroarthrographic signals were collected during knee flexion/extension motion using an accelerator and described by variation of mean square (VMS), mean range (R5), and power spectral density for frequency of 50 to 250 Hz (P1), and 250 to 450 Hz (P2). Patients before viscosupplementation were characterized by about 2-fold higher values of vibroarthrographic parameters than controls. Two weeks after the procedure, the values of R5, P1, and P2 significantly decreased, in comparison to pre-injection. At 4 weeks post-injection, we noted a significant increase in R5, P1, and P2 values, when compared to 2 weeks post-injection. Finally, at 4 weeks post-injection, the level of VMS, R5, and P2 parameters did not differ from values obtained at pre-injection. We showed that viscosupplementation may be effective in providing arthrokinematics improvement, but with a relatively short period of duration. This phenomenon is observed as decreased vibroacoustic emission, which reflects a more smooth movement in the joint.

A New Approach to Treatment of Patellar Chondromalacia; Intra-Articular Injection of Hyaluronic Acid

A New Approach to Treatment of Patellar Chondromalacia; Intra-Articular Injection of Hyaluronic Acid

Fullerene-like MoS2 Nanoparticles as Cascade Catalysts Improving Lubricant and Antioxidant Abilities of Artificial Synovial Fluid.

Intraarticular injection of hyaluronic acid (HA) for viscosupplementation is a nonsurgical therapy for osteoarthritis (OA). However, HA fails to lubricate under a significant load and tends to be depolymerized by the overproduction of reactive oxygen species (ROS) in inflammation. Here, we for the first time reported that fullerene-like MoS2 (F-MoS2) nanoparticles are efficient lubricants and antioxidants for artificial synovial fluid. A model of arthrosis was built, to evaluate the tribological behavior of F-MoS2 nanoparticles. The tests showed that they significantly improve the antiwear and friction-reducing abilities of the artificial synovial fluid. More importantly, the F-MoS2 nanoparticles possess intrinsic dual-enzyme-like activity, mimicking superoxide dismutases (SOD) and catalases (CAT) under physiological conditions (pH 7.4, 25 °C). By coupling of these unique properties, a self-organized cascade catalytic system was constructed, which includes the disproportionation of superoxide radicals (O2•-) to hydrogen peroxide (H2O2) and subsequently the disproportionation of H2O2 into oxygen (O2). The effectiveness of the detox system was evaluated by human umbilical vein endothelial cells (HUVEC) models exposed to oxidative stress. After that, F-MoS2 nanoparticles were used to regulate the ROS level in artificial synovial fluid containing HA. Relative viscosity measurements showed the excellent protective effect of F-MoS2 nanoparticles against HA oxidative damage offered by O2•-. These results indicate that F-MoS2 nanoparticles are promising candidates for treatment of OA and other diseases caused by lubrication deficiency or oxidative stress.

Ultrasound-guided intra-articular injection of hyaluronic acid and ketorolac for osteoarthritis of the carpometacarpal joint of the thumb

Intra-articular hyaluronic acid (HA) is widely used to treat symptomatic osteoarthritis (OA) in the carpometacarpal joint (CMCJ) of the thumb. However, although apparently effective and relatively safe, intra-articular HA injections act relatively slowly. Therefore, a nonsteroidal anti-inflammatory drug could be added for more prompt pain relief. The aim of this study was to compare the efficacy and safety of ultrasound (US)-guided intra-articular injection of HA and ketorolac with that of HA alone in patients with OA of the CMCJ of the thumb.Seventy-four patients identified by chart review to have a diagnosis of OA of the CMCJ of the thumb received either a US-guided intra-articular injection of 0.5 mL of sodium hyaluronate and 0.5 mL of ketorolac (n = 38) or 0.5 mL of sodium hyaluronate and 0.5 mL of saline (n = 36). Disabilities of the arm, shoulder, and hand (DASH) and verbal numeric scale (VNS) pain scores were recorded before and 1, 3, and 6 months after injection. Univariable analyses (using the chi-squared test) and multiple logistic regression analysis were performed to evaluate the relationship between potential predictors of the outcome (treatment allocation, patient age and sex, duration of pain, and Eaton–Littler classification) and therapeutic effects.The DASH and VNS scores were improved at 1, 3, and 6 months postinjection in both groups. The onset of pain relief was significantly more rapid (at 1 month) after the injection containing HA and ketorolac than after the injection containing HA alone. In 55.3% of cases, pain and function were improved postinjection compared with baseline and remained so for up to 6 months. The success rate was not significantly different between the assessments at 1, 3, and 6 months, and the univariable analyses did not identify any statistically significant potential predictors of the outcome. Multiple logistic regression analysis did not identify any independent predictors of a successful outcome at midterm follow-up.The onset of analgesic action was more rapid after an injection containing HA and ketorolac than after 1 containing HA alone in patients with OA of the CMCJ of the thumb. There were no serious complications.

PSU19 ECONOMIC EVALUATION OF DELAYING TKR WITH INTRA-ARTICULAR HYALURONIC INJECTIONS

The objective of this analysis was to compare the direct medial costs between patients who received intra-articular hyaluronic acid (HA) injections prior to total knee replacement (TKR) and patients who did not receive HA injections prior to TKR. A previous study of 22,555 TKR patients using a commercial claims database showed that the time from diagnosis of knee osteoarthritis to TKR surgery was a median of 1.6 years longer for patients receiving HA injections compared to patients not receiving HA injections (p<0.0001) over an 8 year continuous enrollment period. HA patients received an average of 1.7 HA injections over the study period. The number of HA injections and TKR survival curves from this publication were used to quantify the predicted medical costs for hypothetical cohorts of HA (n=500) and non-HA patients (n=500) in an economic model. Direct costs of TKR and HA injections were estimated from the literature and costing algorithms. An annual discount rate of 3% was applied. Cumulative costs over 4 years totaled $11.3 million and $12.7 million in the HA cohort and non-HA cohort, respectively. Costs in the HA cohort were $1.4 million lower than the non-HA cohort over 4 years due to the delay in TKR. The cohorts reached cost-equivalence at 8 years as 98.1% of the HA cohort and 99.1% of the non-HA cohort received a TKR. Costs for HA injections were <4% of total cost in the HA cohort. Results were most sensitive to number of HA series received and least sensitive to changes in HA cost and discount rate. Results are not generalizable to those over age 65 as those patients were not included in the original claims analysis. A cost savings of $1.4 million may be achieved from delaying TKR with HA injections over a 4-year period.

Efficacy and Safety of Intra-articular Injections of Hyaluronic Acid Combined With Polydeoxyribonucleotide in the Treatment of Knee Osteoarthritis.

ObjectiveTo assess the clinical efficacy and safety of intra-articular injection of hyaluronic acid (HA) combined with polydeoxyribonucleotide (PDRN) in patients with knee osteoarthritis in comparison with that of HA alone.MethodsThe current single-center, prospective, randomized, double-blind, controlled study was conducted in 36 patients with knee osteoarthritis at our medical institution. All the eligible patients (n=30) were equally assigned to two treatment arms (trial group ‘HA+PDRN’ and control group ‘HA’). For efficacy assessment, the patients were evaluated for the visual analogue scale (VAS) scores, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Knee Society Scores (KSS), all of which served as efficacy outcome measures. We monitored time-dependent changes in efficacy outcome measures at baseline and 1, 3 and 6 months. Subsequently, we compared differences in changes in efficacy outcome measures at 6 months from baseline between the two groups. Moreover, we assessed the safety based on the treatment-emergent adverse events (TEAEs), adverse drug reactions (ADRs) and any other complications serving as safety outcome measures.ResultsThere were significant differences in changes in the VAS scores, the WOMAC scores in all domains, except ‘Stiffness’, the total WOMAC scores, and the KSS scores in all the domains at 6 months from baseline between the two groups (p<0.05). In our series, there were no TEAEs, ADRs, and any other complications.ConclusionIntra-articular injections of HA combined with PDRN can also be considered in the treatment of knee osteoarthritis. However, further large-scale and multi-center studies are required to demonstrate the potential of the proposed combination.

CCL25-Supplemented Hyaluronic Acid Attenuates Cartilage Degeneration in a Guinea Pig Model of Knee Osteoarthritis.

There is evidence that the application of mesenchymal stromal cells (MSCs) counteracts osteoarthritis (OA) progression. However, the prospect of extracting and expanding these cells might be limited. The aim of this study was to investigate whether hyaluronic acid (HA) supplemented with MSC-recruiting chemokine C-C motif ligand 25 (CCL25) can influence the natural course of spontaneous OA in the guinea pig. CCL25 concentration in synovial fluid (SF) was quantified with enzyme-linked immunosorbent assay. Boyden chamber cell migration assay was used to test CCL25-mediated migration of guinea pig MSC. Forty-nine 11-month-old male guinea pigs were divided into seven groups. The main treatments consisted of five intra-articular injections of HA in pure form and in combination with three doses of CCL25 (63, 693, and 6,993 pg) given at a weekly interval. The severity of cartilage damage was assessed by using a modified Mankin score. The measured average physiological concentration of CCL25 in SF of animals is 85 ± 39 pg/ml. MSC showed a 3.2-fold increase in cell migration at 1,000 nM CCL25 in vitro demonstrating the biological migratory activity of CCL25 on these cells. In vivo, treatment with HA alone did not reduce OA progression. Similarly, OA scores were not found significantly reduced after treatment with 63 pg CCL25 + HA. However, when compared to pure HA, treatment with 693 pg CCL25 + HA and 6,993 pg CCL25 + HA significantly reduced the OA score from 10.1 to 7.4 (-28%) and 8.4 (-20%), respectively. These data suggest that intra-articular injections of HA supplemented with CCL25 attenuates OA. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1723-1729, 2019.

Osteoarthritis of the knee in the elderly: is knee replacement always justified?

Osteoarthritis is a condition that mostly affects the elderly population and tends to be localized to the knee joint. At old age, active treatment options are limited by co-morbidities and a higher risk for surgical complications. Therefore, the search for strategies that could become a temporary alternative to knee replacement is a pressing concern. The aim of this study was to analyze how justifiable is total knee replacement in elderly patients with knee osteoarthritis and to propose a less aggressive therapeutic alternative to this surgery. The study included 178 patients over 60 years of age with clinically established knee osteoarthritis who had been previously recommended knee replacement but chosen not to undergo it. The choice of a treatment strategy tested in the study was based on the original grading scale for the evaluation of the knee joint dislocation syndrome. The treatment consisted of therapeutic arthroscopy and intraarticular injections of hyaluronic acid and platelet-rich plasma (PRP). The data were processed in Statistica 12. Data analysis revealed that 39.3% of the participants did not have compelling indications for knee replacement. The proposed combination therapy with intraarticular PRP injections and arthroscopy allowed all the patients to delay knee replacement for at least a year; unaided by arthroscopy, intraarticular injections worked well for only 40%.

Comparison of the effect of intraarticular hyaluronic acid and effect of naproxen sodium in patients with osteoarthritis of the knee

Purpose: The purpose of this study was to compare the effects of Intraarticular Hyaluronic Acid( IAHA) injection & Naproxen sodium to reduce pain and functional improvement in patient with osteoarthritis of knee. Methods: Randomized clinical trial was conducted in the Department of Physical Medicine and Rehabilitation, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh during the period from November’2015 to October’2016. A number of total 100 patients of OA knee were selected as per inclusion and exclusion criteria. After proper evaluation and clinical examination patients were undergo study procedure and evaluated by selected assessment criteria. All subjects were enrolled after having informed written consent. 100patients were randomly assigned to 2 groups (Group A=50, and Group B=50). Group A: IAHA series of weekly (20mg/2ml each) for 3 weeks, Exercise and ADL instructions and Group B: NSAIDs (Naproxen 500mg) twice daily for four weeks, Exercise and ADL. Respondents of both groups were assessed to at 4th week, 12th week, and 26th week by OA specific translated and validated Bengali instrument- Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire and VAS pain score. The results were expressed as percentage and mean ± SD and level of significance was set at 0.05 and p<0.05 was considered as the level of significant. Student`s t- test and chi-squared (X2) test were done to test the hypothesis which appropriate. Results: 47 patients in group-A and 50 patients in Group-B have completed the study. The improvement of VAS Pain score was 4.02 in group A and 5.62 in group B at week twenty six (26th), which was significant p<0.001. The improvement of WOMAC Pain score was 271.81 in group A and 315.50in group B at week twenty six (26th), which was significant p<0.05.The improvement of WOMAC stiffness score was 107.98 in group A and128.00in group B at week twenty six (26th), which was significant p<0.05. The improvement of WOMAC physical function scorewas 977.66 in group A and B 1314.50in group B at week twenty six (26th), which wassignificant p<0.05. Conclusions: IAHA injection is more beneficial to Naproxen sodium along with exercise and ADL in OA knee.

Evaluation of arthrocentesis with corticosteroids versus arthrocentesis with hyaluronic acid in the management of Temporomandibular joint osteoarthritis

Aim: to evaluate the clinical results, radiographic results and levels of inflammatory mediators following arthrocentesis with intra-articular injection of steroids versus arthrocentesis with intra-articular injection of hyaluronic acid in temporomandibular joint osteoarthritis.Materials and Methods: Ten patients suffering from Osteoarthritis with pain and crepitation during jaw movements together with radiographic evidence of bony erosions were included in the study. The patients were divided into two groups, five patients in group A were treated with arthrocentesis followed by intra-articular injection of corticosteroid and five patients in group B were treated with arthrocentesis followed by intra-articular injection of Hyaluronic acid. Results: Patients in both groups showed significant reduction in pain and increase in maximum mouth opening; however, arthrocentesis with intra-articular injection of HA showed better clinical results compared to arthrocentesis with intra-articular injection of corticosteroids. Less inflammatory mediators were found in the Corticosteroid group patients compared to HA group patients. No evidence of new bone formation was seen in both groups after 4 months postoperatively.Conclusion: Better clinical results were achieved after Arthrocentesis followed by intra-articular injection of hyalurionic acid when compared to arthrocentesis with intra-articular injection of corticosteroids. Less inflammatory mediators were associated with arthrocentesis with corticosteroids injection compared to arthrocentesis with HA injection. Long term follow up is required to be able to assess new bone formation following arthrocentesis with intra-articular injection of HA or corticosteroid.

Do corticosteroids or hyaluronic acid intra-articular injections impact the risk of total knee replacement? Real-life data from the khoala cohort

Do corticosteroids or hyaluronic acid intra-articular injections impact the risk of total knee replacement? Real-life data from the khoala cohort

Radioisotope synovectomy in the treatment of patients with rheumatoid arthritis

In a number of cases, systemic therapy for rheumatoid arthritis (RA), including disease-modifying anti-rheumatic drugs, biological agents, glucocorticoids (GCs), and nonsteroidal anti-inflammatory drugs, fails to completely suppress joint inflammatory changes in the patients. Therefore, local methods are widely used in the combination therapy of RA. Intra-articular injection of hyaluronic acid (HA) is a highly local treatment modality. HA can be used as initial therapy when it is necessary to achieve rapid clinical improvement, or at a later stage of the disease, in exacerbation of arthritis. However, in some patients the effect of intra-articular HA can be short-lasting, and a favorable result can be obtained with local radiotherapy. It is based on powerful irradiation of the inflamed synovium, which is provided by intra-articular injection of radioactive isotope colloids. In Russia, RA was successfully treated with colloidal Au-198, but its production was ceased in the 1990s, and agents for radioisotope synovectomy have been long unavailable. Tungsten-188/Rhenium-188generator has been recently designed in Russia, which allows Rhenium-188 to be obtained in clinics. Preclinical trials have shown that intra-articular injection ensures good fixation of the drug in the knee joint with its insignificant accumulation in the liver and other non-target organs and tissues. Introduction of this drug into routine clinical practice can markedly improve the efficiency of treatment in patients with chronic arthritis.

Effect of steam sterilization and biocompatibility studies of hyaluronic acid hydrogel for viscosupplementation

Intra-articular injection of hyaluronic acid (HA) hydrogel is one of the treatment methods recommended for osteoarthritis (OA). Here HA hydrogel (2000 kDa) has been developed, sterilized by steam sterilization and the important properties required for viscosupplementation such as equilibrium swelling, enzymatic degradation, carbazole assay and rheology analysis has been compared before and after steam sterilization. The effect of steam sterilization was studied by varying the temperature and time of sterilization and a suitable temperature and time such as 118 ₀C for 5 min was optimized. It was found that the optimized sterilization condition does not affect the material properties of HA hydrogel except equilibrium swelling. The stability of the steam sterilized hydrogel was evaluated for 3 months at two different conditions (5 ₀C and 25 ₀C at 60% RH) and it was found that 5 ₀C at 60% RH is the suitable condition of storage. The safety profiles of the HA hydrogel was checked by cytotoxicity analysis, intracutaneous reactivity, acute toxicity studies and found to be biocompatible. Hence It was found the HA hydrogel developed is highly biocompatible, retain its properties after sterilization and is stable upto 3 months when stored at 5 ₀C at 60% RH.

Pseudo-septic arthritis developed after hyaluronic acid injection: A case report

One of the most frequent causes of knee pain is knee osteoarthritis. Intra-articular hyaluronic acid (HA) injection is one of the preferred treatment methods. Although, systemic side effects are not seen, rarely local side effects as pain and swelling can be seen. Following HA injection, some cases with pseudo-septic manifestations unrelated to crystal formation have been reported. In this case report, a patient with knee pain which aggravated with medial tibio-femoral osteoarthritis refractory to conservative treatment methods including administration of non-steroidal anti-inflammatory drugs and others is presented. After intra-articular HA injection, her preexisting knee pain worsened, and swelling, and increase in local temperature were added to the clinical picture. Based on clinical, and laboratory examinations, and analysis of synovial fluid, diagnosis of pseudo- septic arthritis which mimicked manifestations of septic arthritis was made. Clinical, and laboratory improvement was achieved with early treatment. If following intra-articular HA injection, knee pain of the patient aggravates suddenly with local swelling and heat, then the possibility of pseudoseptic arthritis of the affected knee should be always kept in mind.

Cytotoxicity of drugs injected into joints in orthopaedics.

ObjectivesIntra-articular injections of local anaesthetics (LA), glucocorticoids (GC), or hyaluronic acid (HA) are used to treat osteoarthritis (OA). Contrast agents (CA) are needed to prove successful intra-articular injection or aspiration, or to visualize articular structures dynamically during fluoroscopy. Tranexamic acid (TA) is used to control haemostasis and prevent excessive intra-articular bleeding. Despite their common usage, little is known about the cytotoxicity of common drugs injected into joints. Thus, the aim of our study was to investigate the effects of LA, GC, HA, CA, and TA on the viability of primary human chondrocytes and tenocytes in vitro.MethodsHuman chondrocytes and tenocytes were cultured in a medium with three different drug dilutions (1:2; 1:10; 1:100). The following drugs were used to investigate cytotoxicity: lidocaine hydrochloride 1%; bupivacaine 0.5%; triamcinolone acetonide; dexamethasone 21-palmitate; TA; iodine contrast media; HA; and distilled water. Normal saline served as a control. After an incubation period of 24 hours, cell numbers and morphology were assessed.ResultsUsing LA or GC, especially triamcinolone acetonide, a dilution of 1:100 resulted in only a moderate reduction of viability, while a dilution of 1:10 showed significantly fewer cell counts. TA and CA reduced viability significantly at a dilution of 1:2. Higher dilutions did not affect viability. Notably, HA showed no effects of cytotoxicity in all drug dilutions.ConclusionThe toxicity of common intra-articular injectable drugs, assessed by cell viability, is mainly dependent on the dilution of the drug being tested. LA are particularly toxic, whereas HA did not affect cell viability.Cite this article: P. Busse, C. Vater, M. Stiehler, J. Nowotny, P. Kasten, H. Bretschneider, S. B. Goodman, M. Gelinsky, S. Zwingenberger. Cytotoxicity of drugs injected into joints in orthopaedics. Bone Joint Res 2019;8:41–48. DOI: 10.1302/2046-3758.82.BJR-2018-0099.R1.

Intraarticular Injections Before Total Knee Arthroplasty: Risk Factor for Infection?

For patients with knee osteoarthritis, orthopedic guidelines recommend against intraarticular hyaluronic acid injections and note that evidence for

Pharmacokinetics and four-week repeated-dose toxicity of hyaluronic acid and ketorolac combination following intra-articular administration in normal rats

Intra-articular (IA) injection of hyaluronic acid (HA) in combination with nonsteroidal anti-inflammatory drugs, such as ketorolac (KL), have been clinically investigated to provide more rapid and profound pain relief in patients with osteoarthritis. However, its safety, local tolerance, and potential for pharmacokinetic interaction have not been assessed. In this study, the pharmacokinetics and toxicity of a combination of HA and KL were evaluated in normal rats following four-week repeated-dose injection. Rats received HA or KL alone at 4 mg/kg or 16 mg/kg, respectively, or HA/KL combination at 4/4 mg/kg, 4/8 mg/kg, or 4/16 mg/kg on a weekly basis. The rats exhibited temporal, reversible changes in hematology, serum chemistry, and urinalysis caused primarily by KL treatment. No deleterious effects were observed on the joint following repeated IA HA/KL administration, which showed only minimal to mild levels of temporary inflammatory changes in synovial membrane. The plasma KL level following IA injection rose as fast as that of intra-muscular injection, with no alteration with the co-administered HA. In conclusion, repeated IA administration of HA/KL combination was tolerated well in normal rats, encouraging future studies of IA injection of HA/KL combination on osteoarthritis-induced animal models and even patients.

Efficacy, safety, and synovial effects of intra-articular hyaluronic acid in treating recalcitrant hemophilic arthropathy of knee joint

Background and Aim: Recurrent hemarthrosis results in synovitis and destructive arthropathy in hemophilic patients. The aim of our study was to investigate the efficacy and synovial changes with viscosupplementation therapy in treating hemophilic arthropathy of the knee. Subjects and Methods: Twenty hemophilic patients who had painful arthropathy of the knee with synovitis were enrolled. Patients received three weekly intra-articular injections of 2 mL hyaluronic acid (HA). The synovial thickness and vascularity determined by ultrasonography, visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form 36 (SF-36) were compared initially and at 1, 2, 3, and 6 months after the first injection. Statistical analysis was performed using SPSS version 20 software (Armonk, NY, USA: IBM Corp). Results: There were 19 hemophilia A patients and 1 hemophilia B patient. A total of 26 knees received viscosupplementation therapy. Significant improvement in VAS, SF-36, WOMAC score, hyperemia, and thickness of suprapatellar recess synovium from baseline was seen up to 6 months after intra-articular HA injection. No severe injection-related adverse event was observed. Conclusions: This study suggests that three weekly intra-articular HA injections are safe and effective in treating hemophilic arthropathy of knee with synovitis for a period up to 6 months. The treatment not only improved quality of life, pain and knee function but also reduced synovial thickness and hyperemia. HA viscosupplementation therapy could serve as an adjunctive therapy before arthroscopic synovectomy or total knee arthroplasty.