Viscosupplementation is a symptomatic treatment of osteoarthritis (OA) intended to restore rheologic homeostasis of the synovial fluid by injecting hyaluronic acid intraarticularly. Despite the long ...history of this therapy, little is known about its mechanisms of action and differences between commercial preparations. We investigated the rheologic behavior of OA synovial fluid with time, when stored at 4°C, before and after the addition of two hyaluronic acid commercial preparations (linear and cross-linked). Thirteen OA synovial fluids were stored at 4°C and assayed using steric exclusion chromatography, which allows hyaluronic acid to be separated from the remaining pool of proteins and its molecular weight and concentration to be determined without any pretreatment and calibration. The synovial fluid rheology also was studied in vitro, before and after addition of two viscosupplements, over 6 weeks. The non-Newtonian behavior of synovial fluid throughout followup appears to be the result of loose interactions between proteins and hyaluronic acid. When mixed with the linear hyaluronic acid, synovial fluid becomes less non-Newtonian whereas the non-Newtonian behavior was reinforced when mixed with the cross-linked hyaluronic acid. The rheology was nearly unchanged for all synovial fluids over 6 weeks. Our preliminary trial shows it is possible to study synovial fluid, stored at 4°C, over a long time and suggests the enzymatic degradation of hyaluronic acid is negligible under these experimental conditions.
Background:
Early stage of osteoarthritis (OA) is characterized by joint stiffness and pain as well as by subclinical structural changes that may affect cartilage, synovium, and bone. At the moment, ...the lack of a validated definition of early osteoarthritis (EOA) does not allow to make an early diagnosis and adopt a therapeutic strategy to slow disease progression. Also, no questionnaires are available to evaluate the early stage, and therefore this remains an unmet need.
Objective:
Therefore, the purpose of the technical experts panel (TEP) of ‘International Symposium of intra-articular treatment’ (ISIAT) was to create a specific questionnaire to evaluate and monitor the follow-up and clinical progress of patients affected by early knee OA.
Design:
The items for the Early Osteoarthritis Questionnaire (EOAQ) were identified according to the following steps: items generation, items reduction, and pre-test submission.
Methods:
During the first step, literature has been reviewed and a comprehensive list of items about pain and function in knee EOA was drafted. Then, during the ISIAT (5th edition 2019), the draft has been discussed by the board, which reformulated, deleted, or subdivided some of the items. After the ISIAT symposium, the draft was submitted to 24 subjects affected by knee OA. A score based on the importance and the frequency was created and the items with a score ⩾0.75 were selected. After intermediate evaluation made by a sample of patients, the second and final version of the questionnaire EOAQ was submitted to the whole board for final analysis and acceptance in a second meeting (29 January 2021).
Results:
After an exhaustive elaboration, the final version of the questionnaire contains two domains (Clinical Features and Patients Reported Outcome) with respectively 2 and 9 questions, for a total of 11 questions. Questions mainly explored the fields of early symptoms and patients reported outcomes. Marginally, the need of the symptoms treatment and the use of painkillers were investigated.
Conclusions:
Adoption of diagnostic criteria of early OA is strongly encouraged and a specific questionnaire for the whole management of the clinical features and patients’ outcome might really improve the evolution of OA in the early stages of the disease, when the treatment is expected to be more effective.
Interleukin 1 (IL-1) plays a pivotal role in the pathogenesis of osteoarthritis (OA). In animal models of OA, IL-1 blockade by IL-1 receptor antagonist (IL-1Ra) can slow the progression of disease. ...We examined the safety of intraarticular (IA) injections of recombinant human IL-1Ra in patients with knee OA.
A prospective multicenter trial was conducted using the continual reassessment method. Six doses were considered, 0.05 mg up to 150 mg IL-1Ra, and the trial was double-blind regarding the dose administered. Patients with symptomatic knee OA and without synovial fluid effusion were included. Acute inflammatory reaction (the primary endpoint defining intolerance) was recorded if pain increase over 30 mm on 100 mm visual analog scale and synovial fluid effusion occurred within 72 h after the IA injection. As a secondary aim, efficacy was estimated (by total pain and Western Ontario and McMaster University OA functional index) until Month 3.
One patient received 0.05 mg and 13 patients received 150 mg of IL-1Ra. No acute reaction occurred (one patient experienced postinjection joint swelling with no pain) and the 150 mg dose was considered the maximum tolerated dose (intolerance level 0%; confidence interval 0, 9.1%). A significant improvement was still observed until Month 3 in the 13 patients who received 150 mg IL-1Ra: pain improved by -20.4 +/- 23.3 mm (p = 0.008) and WOMAC global score by -19.5 +/- 20.1 (p = 0.005).
IA injection of IL-1Ra in patients with knee OA was well tolerated and did not induce any acute inflammatory reaction. The feasibility of such IA injections of IL-1Ra opens a promising therapeutic perspective for patients with OA.
In this paper, we propose the evaluation of the mannitol's ability to reduce hyaluronic acid (HA) degradation using two different models of oxidative stress. Firstly, a solution of hyaluronan and a ...solution of the same HA including mannitol in PBS buffer were submitted to an oxidative stress generated by the addition of xanthine + xanthine oxidase generating oxygen free radicals. Different enzyme concentrations were used and the HA properties were studied after 24 h of contact at ambient temperature. Decreases of the viscosity of the solution were assessed by rheometry (viscous and elastic module) and that of HA molecular weight was determined by steric exclusion chromatography. Rheologic behavior was assessed on identical HA solutions subjected to another model of oxidative stress imposed by addition of hydrogen peroxide. The influence of mannitol concentration on HA degradation was also demonstrated. Whatever the stress applied, it appears very clearly that mannitol protects hyaluronic acid from mediated oxygen free radicals degradation. These in vitro results suggest that mannitol could be a simple way to significantly increase the intra-articular residence time of the injected hyaluronic acid and therefore might improve viscosupplementation effectiveness.
Osteoarthritis (OA) is the most common form of arthritis, affecting millions of people worldwide and characterised by joint pain and inflammation. It is a complex disease involving inflammatory ...factors and affecting the whole joint, including the synovial membrane. Since drug combination is widely used to treat chronic inflammatory diseases, a similar strategy of designing plant-derived natural products to reduce inflammation in OA joints may be of interest. In this study, we characterised the response of OA synovial cells to lipopolysaccharide (LPS) and investigated the biological action of the combination of curcumin, bromelain and harpagophytum in this original in vitro model of osteoarthritis.
Firstly, human synovial cells from OA patients were stimulated with LPS and proteomic analysis was performed. Bioinformatics analyses were performed using Cytoscape App and SkeletalVis databases. Additionally, cells were treated with curcumin, bromelain and harpagophytum alone or with the three vegetal compounds together. The gene expression involved in inflammation, pain or catabolism was determined by RT-PCR. The release of the encoded proteins by these genes and of prostaglandin E2 (PGE2) were also assayed by ELISA.
Proteomic analysis demonstrated that LPS induces the expression of numerous proteins involved in the OA process in human OA synovial cells. In particular, it stimulates inflammation through the production of pro-inflammatory cytokines (Interleukin-6, IL-6), catabolism through an increase of metalloproteases (MMP-1, MMP-3, MMP-13), and the production of pain-mediating neurotrophins (Nerve Growth Factor, NGF). These increases were observed in terms of mRNA levels and protein release. LPS also increases the amount of PGE2, another inflammation and pain mediator. At the doses tested, vegetal extracts had little effect: only curcumin slightly counteracted the effects of LPS on NGF and MMP-13 mRNA, and PGE2, IL-6 and MMP-13 release. In contrast, the combination of curcumin with bromelain and harpagophytum reversed lots of effects of LPS in human OA synovial cells. It significantly reduced the gene expression and/or the release of proteins involved in catabolism (MMP-3 and -13), inflammation (IL-6) and pain (PGE2 and NGF).
We have shown that the stimulation of human OA synovial cells with LPS can induce protein changes similar to inflamed OA synovial tissues. In addition, using this model, we demonstrated that the combination of three vegetal compounds, namely curcumin, bromelain and harpagophytum, have anti-inflammatory and anti-catabolic effects in synovial cells and may thus reduce OA progression and related pain.
Abstract Objective To identify factors predicting patient satisfaction 2 years after total knee arthroplasty (TKA) for osteoarthritis. Methods Prospective multicenter study of patients followed up ...for 2 years after TKA for osteoarthritis. We evaluated pain and function (Lequesne index and WOMAC) at baseline and after 2 years. After 2 years, the patients rated their satisfaction as a percentage, with values greater than 50% defining good satisfaction. Factors associated with good satisfaction were identified by univariate analyses followed by multivariate analysis. Results Of 299 patients, 264 completed the study (26 were lost to follow-up, six died, and three refused the 2-year evaluation), including 237 (89.8%) with satisfaction scores greater than 50%. Highly significant improvements were found after 2 years versus baseline in the Lequesne index (7.9 vs. 14.5, P < 0.0001) and WOMAC index (26.3 vs. 51.3, P < 0.0001). There were 26 (9.8%) complications. Factors significantly associated with good satisfaction in the multivariate model were absence of complications ( P = 0.004), body mass index less than 27 kg/m2 ( P = 0.015), high radiological joint narrowing score ( P = 0.038), age greater or equal to 70 years ( P = 0.038), and absence of depression at the 2-year evaluation ( P = 0.002). Conclusion We report the first prospective multicenter study done in France to assess pain and function in a large number of patients treated with TKA for osteoarthritis. Our results indicate a high success rate. We identified three factors that predict patient satisfaction and can be assessed before surgery (age greater than 70 years, absence of obesity, and severe joint space narrowing).
Purpose:
The purpose of this study was to obtain information on safety and short-term efficiency of a single intra-articular injection of mannitol-modified cross-linked hyaluronic acid (HANOX-M-XL) ...in patients with painful first metatarsophalangeal joint osteoarthritis (1stMTPJ-OA).
Methods:
The study involved an observational, single-arm, prospective multicentre trial, with a 3-month follow-up. Inclusion criteria were patients with symptomatic 1st MTPJ-OA not relieved by analgesics and / or non-steroidal-anti-inflammatory drugs and / or foot orthotic. All patients received a single, imaging-guided intra-articular (IA) injection of 1 mL of HANOX-M-XL in the 1st MTPJ. The primary outcome was the change in pain between the date of injection and month 3. The secondary outcomes were the patient assessment of effectiveness, the decrease in painkiller use and the influence of the radiographic score on the clinical efficacy.
Results:
Sixty-five participants (72.3% women, mean age = 60) were included in the trial. Coughlin-Shurnas radiological grade was 1 in 28 patients, 2 in 29, and 3 in 6. At baseline and month 3, the average pain (0-10) was 6.5 ± 1.8 and 2.8 ± 2.3, respectively. The change in pain score was highly significant (−3.1 ± 2.9; P < .0001). At baseline there was no statistically difference in pain between the radiological stages (P = .69). At endpoint, the average pain score was 2.0 ± 1.9 in x-ray stage 1, 3.1 ± 2.3 in stage 2 and 3.3 ± 2.4 in stage 3 (P = .001). Mild to moderate adverse reactions were reported by 15 patients. All were a transient increase of the hallux pain that occurred immediately and up to 6 hours after injection and resolved in 1 to 7 days.
Conclusion:
This pilot study suggests that a single IA injection of HANOX-M-XL is safe and mainly benefits patients with mild moderate 1st MTPJ-OA. Further randomized controlled trials are necessary to confirm these preliminary encouraging results.
Purpose
To assess the efficacy and safety of one and two intra-articular (IA) injections of the new viscosupplement, hylastan, compared with a single IA corticosteroid injection for pain due to knee ...osteoarthritis (OA). Hylastan is a high-molecular-weight hyaluronan derivative prepared from bacterial fermented sodium hyaluronate that was developed to remain in the joint for longer than most other viscosupplements.
Methods
This 6-month, double-blind, randomized, parallel group, multicenter trial enrolled patients aged ≥40 years who met American College of Rheumatology criteria for knee OA and had continued pain despite conservative treatment. Patients were randomized 1:1:1 to one of three arms: 2 × 4 mL hylastan (
n
= 129; arthrocentesis then IA hylastan Day 0, same treatment Week 2); 1 × 4 mL hylastan (
n
= 130; arthrocentesis then IA hylastan Day 0, arthrocentesis only Week 2); steroid (
n
= 132; arthrocentesis then IA methylprednisolone acetate 40 mg Day 0, arthrocentesis only Week 2). Participants and evaluators were blinded to treatment. The primary clinical outcome measure was change from baseline in WOMAC A pain score over all postbaseline visits to Week 26.
Results
Statistically significant pain reduction was observed in all three arms, with similar mean (95 % CI) changes in WOMAC A: 2 × 4 mL hylastan −0.9 (−1.0, −0.7); 1 × 4 mL hylastan −0.8 (−0.9, −0.7); steroid −0.9 (−1.0, −0.8); all
P
< 0.0001 versus baseline. Changes in secondary outcomes (OMERACT-OARSI and WOMAC A responder rates, patient/clinical observer global assessments, and WOMAC A1 walking pain) were similar in all three arms. Target knee adverse events were comparable for all treatments.
Conclusions
Both IA hylastan injection regimens were effective in relieving pain with an acceptable safety profile. IA hylastan did not show a difference versus IA corticosteroid; therefore, the hypothesis of superior pain relief was not met. Further research is needed to compare the efficacy and safety of hylastan with other viscosupplements.
Level of evidence
Therapeutic study, Level I.
Ba ckground: The objective of this survey was to assess retrospectively the interest of performing viscosupplementation using imaging guidance in patients suffering from ankle osteoarthritis (OA). ...Patients and methods: This is a multicenter retrospective survey using a standardized questionnaire. Fifty patients suffering from ankle OA and treated, in daily clinical practice, with a single intra-articular injection of a novel viscosupplement made of a combination of a non-animal cross-linked hyaluronan and mannitol, HANOX M-XL, were included in the survey. The injection procedure (imaging or landmark guidance), demographic data, patient's self-evaluation of pain, satisfaction, treatment efficacy, and tolerability were collected. Predictive factors of both efficacy and patient's satisfaction were investigated. Results: The percentages of patients very satisfied/satisfied and not really satisfied/dissatisfied with the treatment were 68% and 32%, respectively. Efficacy was rated as very good, good, moderate, and poor by 38%, 30%, 12%, and 20% of the cases, respectively. Efficacy was unrelated to gender and age and was highly correlated with pain score (P , 0.0001). In satisfied patients, the decrease in consumption of analgesics/non-steroidal anti-inflammatory drugs was .75% in 64% of the cases. Efficacy was significantly different with regard to imaging guidance. There was a statistically significant difference in efficacy and satisfaction between landmark-guided and imaging-guided injections (P = 0.02). The success rate was 2.3 times higher in the imaging-guided group than in the landmark-guided group. No significant difference was found between patients injected under fluoroscopy or ultrasound guidance, despite a trend favoring ultrasound (P = 0.09). Tolerability was rated as very good/good in 47 patients, moderate in two, and poor in one and was unrelated to the type of guidance. Conclusion: This preliminary study suggests that the use of imaging guidance significantly optimizes the success rate of ankle viscosupplementation. No safety concern was observed. Level of evidence: III.
Background:
In this work, we aimed to establish a clinical target in the management of knee osteoarthritis (KOA) and to propose good clinical practice (GCP) statements for carrying out a ...treat-to-target strategy.
Methods:
A steering committee of seven experts had formulated a provisional set of recommendations that were exposed for discussion and modification to a technical expert panel (TEP) of 25 multidisciplinary experts from Europe, North America, South America and Asia. The level of evidence and strength of each recommendation was discussed. The TEP formulated overarching principles and GCP statements based on the level of agreement for each item with a vote using a 10-point numerical scale.
Results:
Two overarching principles and 10 GCP statements were formulated by the TEP. These GCP statements suggest: treatment should achieve clinical improvement bringing the patient to the Patient Acceptable Symptom State (PASS); pharmacological and nonpharmacological treatment should begin as early as possible, with an early diagnosis of symptomatic KOA; the patient should be evaluated every 3–6 months; risk factors of KOA progression should be identified and managed with patients at the beginning of the treatment and monitored regularly; treatment should be adapted according to patient phenotype and disease severity; healthy lifestyle must be promoted and monitored. The level of agreement average ranged from 8.7 to 9.6 on scale.
Conclusions:
The proposed overarching principles and GCP statements have the aim of involving patients, general practitioners and multidisciplinary specialists in sharing a therapeutic treat-to-target strategy for KOA management based on the best evidence and expert opinions.
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