Harnessing the multifunctionality of lipid-based drug delivery systems for the local treatment of osteoarthritis

Osteoarthritis (OA) is a widespread joint condition affecting millions globally, presenting a growing socioeconomic burden thus making the development of more effective therapeutic strategies crucial. This review emphasizes recent advancements in lipid-based drug delivery systems (DDSs) for intra-articular administration of OA therapeutics, encompassing non-steroidal anti-inflammatory drugs, corticosteroids, small molecule disease-modifying OA drugs, and RNA therapeutics. Liposomes, lipid nanoparticles, lipidic mesophases, extracellular vesicles and composite systems exhibit enhanced stability, targeted delivery, and extended joint retention, which contribute to improved therapeutic outcomes and minimized systemic drug exposure. Although active targeting strategies hold promise, further research is needed to assess their targeting efficiency in physiologically relevant conditions. Simultaneously, multifunctional DDSs capable of delivering combinations of distinct therapeutic classes offer synergistic effects and superior OA treatment outcomes. The development of such long-acting systems that resist rapid clearance from the joint space is crucial, where particle size and targeting capabilities emerge as vital factors. Additionally, combining cartilage lubrication properties with sustained drug delivery has demonstrated potential in animal models, meriting further investigation in human clinical trials. This review highlights the crucial need for direct, head-to-head comparisons of novel DDSs with standard treatments, particularly within the same drug class. These comparisons are essential in accurately evaluating their effectiveness, safety, and clinical applicability, and are set to significantly shape the future of OA therapy

GaitSmart motion analysis compared to commonly used function outcome measures in the IMI-APPROACH knee osteoarthritis cohort

[Abstract] Background: There are multiple measures for assessment of physical function in knee osteoarthritis (OA), but each has its strengths and limitations. The GaitSmart® system, which uses inertial measurement units (IMUs), might be a user-friendly and objective method to assess function. This study evaluates the validity and responsiveness of GaitSmart® motion analysis as a function measurement in knee OA and compares this to Knee Injury and Osteoarthritis Outcome Score (KOOS), Short Form 36 Health Survey (SF-36), 30s chair stand test, and 40m self-paced walk test. Methods: The 2-year Innovative Medicines Initiative-Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) knee OA cohort was conducted between January 2018 and April 2021. For this study, available baseline and 6 months follow-up data (n = 262) was used. Principal component analysis was used to investigate whether above mentioned function instruments could represent one or more function domains. Subsequently, linear regression was used to explore the association between GaitSmart® parameters and those function domains. In addition, standardized response means, effect sizes and t-tests were calculated to evaluate the ability of GaitSmart® to differentiate between good and poor general health (based on SF-36). Lastly, the responsiveness of GaitSmart® to detect changes in function was determined. Results: KOOS, SF-36, 30s chair test and 40m self-paced walk test were first combined into one function domain (total function). Thereafter, two function domains were substracted related to either performance based (objective function) or self-reported (subjective function) function. Linear regression resulted in the highest R2 for the total function domain: 0.314 (R2 for objective and subjective function were 0.252 and 0.142, respectively.). Furthermore, GaitSmart® was able to distinguish a difference in general health status, and is responsive to changes in the different aspects of objective function (Standardized response mean (SRMs) up to 0.74). Conclusion: GaitSmart® analysis can reflect performance based and self-reported function and may be of value in the evaluation of function in knee OA. Future studies are warranted to validate whether GaitSmart® can be used as clinical outcome measure in OA research and clinical practice

Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period

Trial registration number NCT02709486[Abstract] Objective. Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up. Methods. This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient’s Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study. Results. From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE –0.62±0.18, p=0.0006), WOMAC Physical Function (–0.71±0.17, p<0.0001) and PGA-OA (–0.19±0.07, p=0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function, but not PGA-OA. Rapidly progressive osteoarthritis (RPOA) was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%–7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoaesthesia (both doses) than placebo. Conclusion. Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups

A rush to judgment? Rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for COVID-19

Funding Information: Disclosures: Dr. Kim reports personal fees from Exagen Diagnostics and GlaxoSmithKline and grants from the National Institutes of Health and the Rheumatology Research Foundation outside the submitted work. Dr. Sparks reports grants from the National Institute of Allergy and Infectious Diseases Autoimmune Centers of Excellence, National Institutes of Health, during the conduct of the study and personal fees from Bristol-Myers Squibb, Gilead, Inova, Janssen, and Optum outside the submitted work. Dr. Berenbaum reports personal fees from Boehringer, Bone Therapeutics, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, No-vartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, TRB Chemedica, and 4P Pharma outside the submitted work. Dr. Korsten reports personal fees from GlaxoSmith-Kline, Sanofi-Aventis, Pfizer, AbbVie, Novartis Pharma, Lilly, and Bristol-Myers Squibb outside the submitted work. Dr. Sat-tui reports funding from a Vasculitis Clinical Research Consortium (VCRC)/Vasculitis Foundation Fellowship. The VCRC is part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Science (NCATS). The VCRC is funded through collaboration between NCATS and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319). Dr. Ugarte-Gil reports grants from Pfizer and Janssen outside the submitted work. Dr. Grainger reports nonfinancial support from Pfizer Australia and Janssen Australia and personal fees from Pfizer Australia, Cornerstones, Janssen New Zealand, and Novartis outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www .acponline.org/authors/icmje/ConflictOfInterestForms.do?ms Num=M20-1223.publishersversio

Baseline clinical characteristics of predicted structural and pain progressors in the IMI-APPROACH knee OA cohort

[Abstract] Objectives: To describe the relations between baseline clinical characteristics of the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) participants and their predicted probabilities for knee osteoarthritis (OA) structural (S) progression and/or pain (P) progression. Methods: Baseline clinical characteristics of the IMI-APPROACH participants were used for this study. Radiographs were evaluated according to Kellgren and Lawrence (K&L grade) and Knee Image Digital Analysis. Knee Injury and Osteoarthritis Outcome Score (KOOS) and Numeric Rating Scale (NRS) were used to evaluate pain. Predicted progression scores for each individual were determined using machine learning models. Pearson correlation coefficients were used to evaluate correlations between scores for predicted progression and baseline characteristics. T-tests and χ2 tests were used to evaluate differences between participants with high versus low progression scores. Results: Participants with high S progressions score were found to have statistically significantly less structural damage compared with participants with low S progression scores (minimum Joint Space Width, minJSW 3.56 mm vs 1.63 mm; p<0.001, K&L grade; p=0.028). Participants with high P progression scores had statistically significantly more pain compared with participants with low P progression scores (KOOS pain 51.71 vs 82.11; p<0.001, NRS pain 6.7 vs 2.4; p<0.001). Conclusions: The baseline minJSW of the IMI-APPROACH participants contradicts the idea that the (predicted) course of knee OA follows a pattern of inertia, where patients who have progressed previously are more likely to display further progression. In contrast, for pain progressors the pattern of inertia seems valid, since participants with high P score already have more pain at baseline compared with participants with a low P score

Relationship Between Motion, Using the GaitSmartTM System, and Radiographic Knee Osteoarthritis: An Explorative Analysis in the IMI-APPROACH Cohort

Multicenter study[Abstract] Objectives: To assess underlying domains measured by GaitSmartTMparameters and whether these are additional to established OA markers including patient reported outcome measures (PROMs) and radiographic parameters, and to evaluate if GaitSmart analysis is related to the presence and severity of radiographic knee OA. Methods: GaitSmart analysis was performed during baseline visits of participants of the APPROACH cohort (n = 297). Principal component analyses (PCA) were performed to explore structure in relationships between GaitSmart parameters alone and in addition to radiographic parameters and PROMs. Logistic and linear regression analyses were performed to analyse the relationship of GaitSmart with the presence (Kellgren and Lawrence grade ≥2 in at least one knee) and severity of radiographic OA (ROA). Results: Two hundred and eighty-four successful GaitSmart analyses were performed. The PCA identified five underlying GaitSmart domains. Radiographic parameters and PROMs formed additional domains indicating that GaitSmart largely measures separate concepts. Several GaitSmart domains were related to the presence of ROA as well as the severity of joint damage in addition to demographics and PROMs with an area under the receiver operating characteristic curve of 0.724 and explained variances (adjusted R2) of 0.107, 0.132 and 0.147 for minimum joint space width, osteophyte area and mean subchondral bone density, respectively. Conclusions: GaitSmart analysis provides additional information over established OA outcomes. GaitSmart parameters are also associated with the presence of ROA and extent of radiographic severity over demographics and PROMS. These results indicate that GaitsmartTM may be an additional outcome measure for the evaluation of OA

Report from the Hand Osteoarthritis Working Group at OMERACT 2018: Update on Core Instrument Set Development

Objective: To evaluate hand osteoarthritis tools for core instrument set development. Methods: For OMERACT 2018, a systematic literature review and advances in instrument validation were presented. Results: Visual analog and numerical rating scales were considered valuable for pain and patient’s global assessment, despite heterogeneous phrasing and missing psychometric evidence for some aspects. The Modified Intermittent and Constant Osteoarthritis Pain scale was lacking evidence. The Michigan Hand Outcomes Questionnaire had advantages above other pain/function questionnaires. The Hand Mobility in Scleroderma scale was valid, although responsiveness was questioned. Potential joint activity instruments were evaluated. Conclusion: The development of the core instrument set is progressing, and a research agenda was also developed

EULAR points to consider for the development, evaluation and implementation of mobile health applications aiding self-management in people living with rheumatic and musculoskeletal diseases

Background: Mobile health applications (apps) are available to enable people with rheumatic and musculoskeletal diseases (RMDs) to better self-manage their health. However, guidance on the development and evaluation of such apps is lacking. Objectives: The objective of this EULAR task force was to establish points to consider (PtC) for the development, evaluation and implementation of apps for self-management of RMDs. Methods: A systematic literature review of app content and development strategies was conducted, followed by patient focus group and an online survey. Based on this information and along with expert opinion, PtC were formulated in a face-to-face meeting by a multidisciplinary task force panel of experts, including two patient research partners. The level of agreement among the panel in regard to each PtC was established by anonymous online voting. Results: Three overarching principles and 10 PtC were formulated. Three PtC are related to patient safety, considered as a critical issue by the panel. Three were related to relevance of the content and functionalities. The requirement for transparency around app development and funding sources, along with involvement of relevant health professionals were also raised. Ease of app access across ages and abilities was highlighted, in addition to considering the cost-benefit of apps from the outset. The level of agreement was from 8.8 to 9.9 out of 10. Conclusion: These EULAR PtC provide guidance on important aspects that should be considered for the development, evaluation and implementation of existing and new apps