Predictors of Clinical Benefit with Intra-articular Hyaluronic Acid in Patients with Knee Osteoarthritis - A Narrative Review.

BACKGROUND: There is conflicting evidence regarding the efficacy of viscosupplementation with intra-articular hyaluronic acid injections in knee osteoarthritis. One possible explanation for the inconsistent findings on its efficacy is that only certain subpopulations of patients benefit from this therapy. OBJECTIVE: The purpose of this narrative review is to succinctly summarize the existing data on the predictive factors of clinical response to intra-articular hyaluronic acid to identify the patient profile most likely to benefit from this therapy. METHODS: For this narrative review, a PubMed search was conducted in January 2023, with no date limits, to identify publications reporting predictive factors of response to viscosupplementation using the following terms: hyaluronic acid OR viscosupplem* AND osteoarthritis AND knee AND predict*. Searches were limited to randomized controlled trials, systematic reviews and meta- analyses, or observational studies written in English. Other relevant references were identified by searching the references of retrieved articles. RESULTS: The disease severity was found to reliably predict response to intra-articular hyaluronic acid injections; patients with less severe diseases consistently had a more robust therapeutic response than those with more severe diseases. Other clinical variables such as level of baseline pain did not reliably predict response. Body mass index, and possibly age, may also be independent predictors of the response. CONCLUSION: A review of the existing literature suggests that patients with less severe clinical symptoms and radiological findings, who are younger, and with a lower or normal body mass index are the best candidates for intra-articular hyaluronic acid therapy.

What We Should Expect from an Innovative Intra-Articular Hyaluronic Acid Product: Expert Opinion Based on a Comprehensive Review of the Literature.

BACKGROUND: Intra-articular hyaluronic acid (IAHA) products are often used in the treatment of adults with mild-to-moderate knee osteoarthritis (KOA). The International Symposium on Intra-Articular Treatment (ISIAT) convened a multidisciplinary technical expert panel to define characteristics for an innovative IAHA product that should answer unmet needs in the clinical management of adults with mild-to-moderate KOA. METHODS: An initial set of evidence-based statements was developed based on data extracted from articles identified through a comprehensive literature search. A Delphi panel comprising 19 experts in KOA voted in 3 rounds to rate their degree of agreement with accepted statements. RESULTS: The final set of 13 accepted statements focus on the effect of an innovative IAHA across 5 key domains of nociceptive pain, joint function, quality of life, joint structure and integrity, and adverse effects. The statements set thresholds for clinically meaningful improvements that exceed those generally achievable by currently available IAHA products. CONCLUSION: The characteristics described by these statements from the ISIAT set new standards for what should be expected from an innovative IAHA. These statements should serve as a framework for driving the development of innovative IAHA products that will surpass the actual outcomes achieved by current viscosupplements in patients with mild-to-moderate KOA.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Early Osteoarthritis Questionnaire (EOAQ): a tool to assess knee osteoarthritis at initial stage.

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.

Self-organization and dewetting kinetics in sub-10 nm diblock copolymer line/space lithography.

In this work, we investigated the self-assembly of a lamellar block copolymer (BCP) under different wetting conditions. We explored the influence of the chemical composition of under-layers and top-coats on the thin film stability, self-assembly kinetics and BCP domain orientation. Three different chemistries were chosen for these surface affinity modifiers and their composition was tuned in order to provide either neutral wetting (i.e. an out-of-plane lamellar structure), or affine wetting conditions (i.e. an in-plane lamellar structure) with respect to a sub-10 nm PS-b-PDMSB lamellar system. Using such controlled wetting configurations, the competition between the dewetting of the BCP layer and the self-organization kinetics was explored. We also evaluated the spreading parameter of the BCP films with respect to the configurations of surface-energy modifiers and demonstrated that BCP layers are intrinsically unstable to dewetting in a neutral configuration. Finally, the dewetting mechanisms were evaluated with respect to the different wetting configurations and we clearly observed that the rigidity of the top-coat is a key factor to delay BCP film instability.

EUROVISCO Good Practice Recommendations for a First Viscosupplementation in Patients with Knee Osteoarthritis.

RATIONALE: Viscosupplementation (VS) with hyaluronic acid is widely used in the management of knee osteoarthritis. There is no clear recommendation on the decision-making to achieve VS. DESIGN: Based on extensive research of the literature and expert opinion, the members of the EUROVISCO (European Viscosupplementation Consensus Group) task force were asked to give their degree of agreement with 60 issues, using a Delphi method. RESULTS: The expert panel achieved unanimous agreement in favor of the following statements: It is recommended to assess pain on a visual or 10-point numeric scale before considering VS. VS can be considered for patients with pain scores between 3 and 8. A standard x-ray must be obtained before the decision of VS. If the x-ray is normal, osteoarthritis must be confirmed by MRI or computed tomography (CT) arthrogram before considering VS. The aims of VS are relieving pain, improving function, and reducing non-steroidal anti-inflammatory drug (NSAID) consumption. The use of VS must not be considered for treating an osteoarthritis flare. VS can be envisaged as a first-line pharmacological treatment in patients having a contra-indication to NSAIDs or analgesics. VS can be considered in patients with contra-indications to arthroplasty. In the case of severe comorbidities (diabetes, hypertension, gastrointestinal disorders, renal failure), VS can avoid the use of potentially dangerous treatments. VS can be considered in patients receiving antiplatelet agents, vitamin K antagonists, and direct factor Xa or thrombin inhibitors. Five other statements obtained a high level of consensus. CONCLUSION: These recommendations, illustrated in a decision algorithm, have been established to help practitioners in the decision-making of knee VS.

Calcific tendinopathy: an unexpected side effect of tyrosine kinase inhibitor?

Musculoskeletal (MSK) pains have been reported during TKI treatment or after its discontinuation in patients with chronic myeloid leukemia (CML). We hypothesized that MSK pains originate from calcific tendinopathy according to preliminary clinical observations. We conducted a retrospective study including CML patients divided into three groups: patients with MSK pain during TKI treatment; asymptomatic patients during TKI treatment; patients with MSK pain after TKI discontinuation. Patients with MSK pain were clinically evaluated, and the presence of calcific deposits was assessed in X-rays of both shoulders and pelvis. Forty-five patients were included; 14 described MSK pain during TKI treatment and 12 after TKI discontinuation. A diagnosis of rotator cuff tendinopathy was retained for 57.7% of patients and of gluteus tendinopathy in 19.2%. The prevalence of calcifications in shoulders and/or hips was 64.3% in symptomatic patients receiving TKIs, 63.2% in asymptomatic patients and 75.0% in patients with MSK pain after TKI treatment.

MRI and ultrasonography for detection of early interphalangeal osteoarthritis.

OBJECTIVES: To assess the interest of MRI and ultrasonography (US) in identifying early and advanced interphalangeal (IP) OA. METHODS: We conducted a case-control study including patients with symptomatic hand OA (n=33) and young healthy volunteers (n=26). Proximal and distal IP joints were graded according to Kellgren and Lawrence (KL) grades. In OA patients, we separated IP joints into 2 groups: "at risk of OA" joints (potential early pre-radiographic OA joints, KL=0) and OA joints (KL=2-4). All IP joints from healthy participants were KL=0 and were considered strictly normal IP joints. Concurrently, synovitis, effusion, erosions, osteophytes, bone marrow lesions, cysts and cartilage space loss were graded by MRI and/or US. We assessed their prevalence, severity and diagnostic performance in hand OA and then compared normal IP joints from healthy participants and "at risk of OA" IP joints from OA patients as well as "at risk of OA" and OA IP joints from OA patients. RESULTS: The prevalence and grade of most MRI/US-detected lesions were higher in IP joints from OA patients than healthy participants. Except for osteophyte assessment, MRI seemed more sensitive than US. We found more MRI/US-detected lesions in "at risk of OA" IP joints than normal joints but also in OA than "at risk of OA" joints from OA patients. US appeared both sensitive and specific for detecting osteophytes in joints without radiographic abnormalities. CONCLUSIONS: MRI and US give good performance for detecting radiographic and pre-radiographic OA lesions and could be interesting tools to identify early hand OA.

Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence.

Knee osteoarthritis (KOA) is a debilitating disease characterized by chronic pain, stiffness, and decreased mobility. Intra-articular injectable therapies show good clinical efficacy in improving symptoms; however, these therapies and their comparators (intra-articular saline) have been associated with a large underlying placebo effect. We aimed to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect in clinical trials in KOA. A targeted literature review was conducted by searching Embase, MEDLINE®, and CENTRAL using predefined study selection criteria. All eligible studies identified were extracted for relevant data, and results were narratively summarized. Forty-three studies were included following screening. Challenges associated with the intra-articular placebo effect included its ability to mask the comparative efficacy of active treatments in trials (n = 7 studies), long-lasting effects (up to 6 months; n = 3), and substantial variation of placebo effect sizes across populations (n = 3). Hypotheses for the mechanism of the placebo effect included aspiration of synovial fluid during administration (n = 6) and dilution of inflammatory mediators (n = 2). Factors affecting the placebo effect size were more invasive routes of administration (e.g., injection versus oral; n = 4) and patient expectations (n = 2). Proposed solutions included the suggestion for readers to weigh the relevance of clinical trial evidence against the presence of large underlying placebo effects (n = 9), discontinuation of intra-articular saline as an appropriate placebo (n = 5), and inclusion of 'no treatment' or sham injection as a control (n = 4). The intra-articular placebo effect is a well-documented occurrence in KOA clinical trials, and it is suggested that it be accounted for when designing randomized controlled trials. Awareness and understanding of the intra-articular placebo effect in KOA are required for fair interpretation of clinical trial evidence.

Systematic Literature Review and Expert Opinion for the Use of Viscosupplementation with Hyaluronic Acid in Different Localizations of Osteoarthritis.

Osteoarthritis (OA) is a significant cause of disability. Considering the increasing diffusion of the viscosupplementation (VS) with hyaluronic acid (HA), the International Symposium Intra Articular Treatment (ISIAT) appointed a Technical Expert Panel (TEP) to identify the criteria for successful VS with a specific HA in OA; this through a systematic literature review (SLR), performed following the PRISMA guidelines interrogating Medline, Embase, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Grey Matters and American College of Rheumatology (ACR/EULAR) databases and the opinion of international experts. The research included only studies on adults and humans without limitations of language or time of publication. Researchers extracted both quantitative and qualitative data from each study. Mixed Methods Appraisal Tool (MMAT) was used to perform quality analysis for the level of evidence. The SLR retrieved 385 papers, 25 of which were suitable for the analysis. The TEP focused on the different formulations of the product Sinovial® [HA 0.8%, HA 1.6%, HA 2%, 800-1200 kDa, HA 3.2% (1400-2100 kDa/65-110 kDa)]. The choice was due to the vast amount of evidence available. The TEP weighed the evidence in two rounds of a Delphi survey; the results, and any disagreement, were discussed in a final session. Three domains were considered: 1) the patients' characteristics associated with the best results; 2) the contraindications and the conditions linked to increased risk of failure; 3) the clinical conditions in which VS is considered appropriate. The TEP concluded that VS with HA is safe and effective in the treatment of knee and hip OA of grades I to III and that it is possible to undertake VS in other situations (eg grade IV Kellgren-Lawrence - KL); a comprehensive examination of the patient should be performed before the procedure.

Dry-Etching Processes for High-Aspect-Ratio Features with Sub-10 nm Resolution High-χ Block Copolymers.

Directed self-assembly of block copolymers (BCP) is a very attractive technique for the realization of functional nanostructures at high resolution. In this work, we developed full dry-etching strategies for BCP nanolithography using an 18 nm pitch lamellar silicon-containing block copolymer. Both an oxidizing Ar/O2 plasma and a nonoxidizing H2/N2 plasma are used to remove the topcoat material of our BCP stack and reveal the perpendicular lamellae. Under Ar/O2 plasma, an interfacial layer stops the etch process at the topcoat/BCP interface, which provides an etch-stop but also requires an additional CF4-based breakthrough plasma for further etching. This interfacial layer is not present in H2/N2. Increasing the H2/N2 ratio leads to more profound modifications of the silicon-containing lamellae, for which a chemistry in He/N2/O2 rather than Ar/O2 plasma produces a smoother and more regular lithographic mask. Finally, these features are successfully transferred into silicon, silicon-on-insulator, and silicon nitride substrates. This work highlights the performance of a silicon-containing block copolymer at 18 nm pitch to pattern relevant hard-mask materials for various applications, including microelectronics.

Retreatment with Hyaluronic Acid Viscosupplementation in Knee Osteoarthritis: Agreement between EUROVISCO Guidelines and Current Medical Practice.

OBJECTIVES: This work studied if and how current clinical practice agrees with European Viscosupplementation Consensus Group (EUROVISCO) recommendations and how this agreement might be different according to physician's specialization. In addition, this work aimed to identify key decision factors that practitioners consider in their decision to retreat or not a patient with hyaluronic acid viscosupplementation. METHODS: Practitioners have been invited by e-mail to participate in an online exercise on viscosupplementation retreatment. They received a fictional patient case at random among a set of predefined fictional cases. The platform asked the practitioner if he/she would retreat the patient with viscosupplementation or not. To take a decision, the practitioner could select questions among a list of predefined questions. Among them, some were related to criteria used in the EUROVISCO decision tree and others served as confounding factors. RESULTS: A total of 506 practitioners participated to the exercise, of which 399 gave their decision about the case assigned to them by the platform. The observed agreement between practitioner decisions and EUROVISCO recommendations was 58.89 ± 4.95% (95% confidence interval [CI]). Overall, the decision to retreat was taken in 47.87% of the cases, while the EUROVISCO guidelines follow-up would have led to 55.89% retreatment for the same cases (P = 0.03). CONCLUSIONS: In current practice, physicians tended to reinject their patients less than recommended, although EUROVISCO guidelines for viscosupplementation retreatment consider decision criteria that clearly correspond to those of practitioners in real life. These include the patients' willingness to be treated or the patients' perception of the effectiveness of the treatment.

Viscosupplementation for the treatment of osteoarthritis. The contribution of EUROVISCO group.

Viscosupplementation (VS) is a symptomatic treatment for knee and other joint osteoarthritis (OA). Despite a long history of use, conflicting opinions remain on the best clinical indications and the most appropriate patients to be treated with intra-articular hyaluronic acid (IA-HA), the optimal dosing regimen and the modalities of retreatment. A multidisciplinary committee of European experts on OA (EUROVISCO) was constituted to formulate recommendations, aimed at helping physicians in the decision-making and the optimal achievement of VS. Before each session members were tasked to collate an exhaustive literature review. Level of evidence and strength of recommendation were based on the level of agreement for each item according to the Delphi method. In 2015, a consensus position was proposed for 24 statements. Among those that obtained a consensual agreement, the working group stressed that VS is effective in mild/moderate knee OA but is not an alternative to surgery in advanced OA, and that dosing regimen must be supported by controlled trials. In 2018, two decision algorithms for the retreatment with IA-HA in knee OA were published. Among the key recommendations, the experts recommended to re-treat every year patients with high risk of OA progression, even if not symptomatic. In 2020, EUROVISCO published two sets of recommendations for the design of clinical trials on the disease-modifying effect of VS and for optimizing the results of VS. The working group underlined that an accurate analysis of radiological features and symptoms and a careful clinical examination may improve the chances of success of VS, as well as good technique of injection and the use of imaging guidance. Based on the exhaustive analysis of the literature and their own clinical experience, the EUROVISCO experts offer a wide range of recommendations intended to help practitioners, particularly in certain cases where the specific characteristics of the patients make the therapeutic decision difficult.

The DIGICOD cohort: A hospital-based observational prospective cohort of patients with hand osteoarthritis - methodology and baseline characteristics of the population.

OBJECTIVE: Despite its prevalence, there are few worldwide hand osteoarthritis (HOA) cohorts. The main objective of DIGItal COhort Design (DIGICOD) cohort is to investigate prognostic clinical, biological, genetic and imaging factors of clinical worsening after 6years follow-up. METHODS: DIGICOD is a hospital-based prospective cohort including patients>35years-old with symptomatic HOA fulfilling: (i) ACR criteria for HOA with≥2 symptomatic joints among proximal/distal interphalangeal joints or 1st interphalangeal joint with Kellgren-Lawrence (KL)≥2; or (ii) symptomatic thumb base OA with KL≥2. Main exclusion criteria were inflammatory arthritis and crystal arthropathies. Annual clinical evaluations were scheduled with imaging (X-rays of the hands and of other OA symptomatic joints) and biological sampling every 3years. Hand radiographs are scored using KL and anatomical Verbruggen-Veys scores. Follow-up visits are ongoing. Cohort methodology and baseline characteristics are presented. RESULTS: Between April 2013 and June 2017, from the 436 HOA included patients, 426 have been analysed of whom 357 (84%) are women. Mean age±standard deviation was 66.7±7.3years and mean disease duration was 12.6±9.6years. Metabolic syndrome affected 151 (36.5%) patients. Mean Visual Analog Scale (VAS) hand pain (0-100mm) was 44.4±26.7mm at activity. Mean FIHOA (0-100) was 19.9±18.6. Elevated serum CRP level (≥5mg/L) involved 10% patients. Mean KL score (0-128) was 46.7±18 and the mean number of joint with KL≥2 was 15.1±6.3. Erosive HOA (defined as≥1 Erosive or Remodeling phase joint according to Verbruggen-Veys score) involved 195/426 (45.8%) patients and the median number (interquartile range) of erosive joints in erosive patients was 3.0 (1.0-5.0). CONCLUSION: DIGICOD is a unique prospective HOA cohort with a long-term 6years standardized assessment and has included severe radiologically HOA patients with a high prevalence of erosive disease.

Lithographically Defined Cross-Linkable Top Coats for Nanomanufacturing with High-χ Block Copolymers.

The directed self-assembly (DSA) of block copolymers (BCPs) is a powerful method for the manufacture of high-resolution features. Critical issues remain to be addressed for successful implementation of DSA, such as dewetting and controlled orientation of BCP domains through physicochemical manipulations at the BCP interfaces, and the spatial positioning and registration of the BCP features. Here, we introduce novel top-coat (TC) materials designed to undergo cross-linking reactions triggered by thermal or photoactivation processes. The cross-linked TC layer with adjusted composition induces a mechanical confinement of the BCP layer, suppressing its dewetting while promoting perpendicular orientation of BCP domains. The selection of areas of interest with perpendicular features is performed directly on the patternable TC layer via a lithography step and leverages attractive integration pathways for the generation of locally controlled BCP patterns and nanostructured BCP multilayers.

Bone Status According to Neurofibromatosis Type 1 Phenotype: A Descriptive Study of 60 Women in France.

There is an increased risk of osteoporosis and an abnormal bone turn over in neurofibromatosis 1 (NF1). Our objective is to evaluate bone status in NF1 and to look for associations with cutaneous phenotype. We conducted a descriptive, monocentric study. We included 60 NF1 women, 18-51 years old, non-menopausal, divided in 2 groups: «at risk phenotype¼ (ARP) composed by 30 patients with at least 2 subcutaneous neurofibromas (SC-NF) and «classical phenotype¼ (CP) composed by 30 patients with none or 1 SC-NF. We evaluated low bone mineral density (BMD) risk factors and measured BMD, calcium and phosphorus homeostasis and bone turnover markers. Before 50 years old, Z-score has to be used to assess BMD. Z-score < - 2 is below expected range and represents 2.5% of the population. There was no difference between the two groups. Overall, Z-scores were low and 5 patients had a Z-score < - 2 (8.3%), which is 3 times general population low BMD frequency. 10 fragility fractures occurred in 8 patients, among which 2 were vertebral fractures. 85% had low calcium intake. 12 patients had hypophosphoremia, 25 elevated PTH. Vitamin D levels were low for 86.4%. 41 patients (69.5%) had at least one abnormal bone turnover markers. Low BMD is 3.3 times more frequent in NF1 than in general population, with high fracture risk, regardless of the skin phenotype, classical or at risk, because of high bone turn over and secondary hyperparathyroidism due to vitamin D deficiency and poor calcium intake.

Intraarticular Corticosteroids for Hip Osteoarthritis: A Review.

INTRODUCTION: Hip osteoarthritis is a prevalent condition responsible for important pain and disability. Most available guidelines for nonsurgical management of hip osteoarthritis recommend a combination of nonpharmacological and pharmacological treatment modalities. Intraarticular corticosteroid injections have been used for decades, although evidence is quite scarce, and many controversies remain. METHODS: This article reviews the available literature from Medline and Embase and discusses the evidence for intraarticular corticosteroid injections in hip osteoarthritis, where only 5 randomized controlled trials were found in the literature. These are analyzed in this article, which also aims to explain the main characteristics and features of glucocorticoids, along with their contraindications and potential adverse effects. RESULTS: Available randomized controlled trials show that intraarticular corticosteroid injections provide pain relief and functional improvement in hip osteoarthritis. This efficacy has not been shown with intraarticular hyaluronic acid injections. CONCLUSION: This review shows that intraarticular corticosteroid injections are efficacious in hip osteoarthritis and that this benefit can last up to 12 weeks.