Prospects of Disease-Modifying Osteoarthritis Drugs.

Osteoarthritis (OA) causes a massive disease burden with a global prevalence of nearly 23% in 2020 and an unmet need for adequate treatment, given a lack of disease-modifying drugs (DMOADs). The author reviews the prospects of active DMOAD candidates in the phase 2/3 clinical trials of drug development pipeline based on key OA pathogenetic mechanisms directed to inflammation-driven, bone-driven, and cartilage-driven endotypes. The challenges and possible research opportunities are stated in terms of the formulation of a research question known as the PICO approach: (1) population, (2) interventions, (3) comparison or placebo, and (4) outcomes.

Comparison of ultrasound guidance with landmark guidance for symptomatic benefits in knee, hip and hand osteoarthritis: Systematic review and meta-analysis of randomised controlled trials.

Introduction: More than half of the patients with moderate and severe osteoarthritis (OA) report unsatisfactory pain relief, requiring consideration of intra-articular (IA) injections as the second-line management. Ultrasound-guided IA injection has proven evidence of higher accuracy in administering IA injectates into the joints than landmark-guided or blind IA injections. However, questions remain about translating higher accuracy rates of ultrasound-guided injection into better clinical improvements. Therefore, we examined the symptomatic benefits (pain, function and patient satisfaction) of ultrasound-guided injection in knee, hip and hand OA compared with blind injections by synthesising a systematic review and meta-analysis of randomised controlled trials (RCT). Methods: PubMed, Medline and Embase databases were searched for eligible studies from their inception to August 28, 2023. Results: Out of 295 records, our meta-analysis included four RCTs (338 patients with knee OA), demonstrating significant improvement in procedural pain [-0.89 (95% CI -1.25, -0.53)], pain at follow-up [-0.51 (95% CI -0.98, -0.04)] and function [1.30 (95% CI 0.86, 1.73)], favouring ultrasound guidance. One single study showed higher patient satisfaction with ultrasound guidance. Conclusion: Ultrasound-guided IA injection provided superior clinical outcomes compared with landmark-guided IA injection.

Efficacy and safety of pentosan polysulfate sodium in people with symptomatic knee osteoarthritis and dyslipidaemia: protocol of the MaRVeL trial.

INTRODUCTION: Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia. METHODS AND ANALYSIS: MaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750.

New therapeutic strategies in osteoarthritis.

Osteoarthritis (OA) is the most prevalent arthritis-type and is a major contributor to chronic joint pain, impaired physical function, and limited mobility. By the end of 2020, a total of 595 million, equal to 7·6% of the global population, had OA; this figure is expected to rise exponentially by 2050. Even while the disorder's intricate pathophysiology is starting to appear intelligible, we are yet to have a cure for the disorder. OA is typically managed with traditional palliative measures, such as topical and systemic analgesics, including non-steroidal anti-inflammatory drugs, therapeutic exercise, and braces. Sometimes, intra-articular glucocorticoids, viscosupplementation, or regenerative interventions provide short-term pain relief and functional improvement; some may require arthroplasty. Researchers continue their efforts to unveil a new therapeutic target to be effective in OA that modifies symptoms and arrests disease progression as well. In the present literature review, insights into new therapeutic strategies in OA, for example, liposome-based dexamethasone, microspore-based triamcinolone, nerve growth factor antagonist, anti-ADAMTS-5 (A Disintegrin And Metalloproteinase Thrombospoidin Motifs - 5), pentosan polysulfate sodium, allogeneic stem cells, C-C chemokine receptor type-4 (CCR4) ligand 17 inhibitor, Wnt-signaling inhibitor, and anti-obesity medications are provided.

Sex differences in osteoarthritis prevalence, pain perception, physical function and therapeutics.

OBJECTIVE: Women have a higher prevalence of osteoarthritis (OA) and worse clinical courses than men. However, the underlying factors and therapeutic outcomes of these sex-specific differences are incompletely researched. This review examines the current state of knowledge regarding sex differences in OA prevalence, risk factors, pain severity, functional outcomes, and use and response to therapeutics. METHODS: PubMed database was used with the title keyword combinations "{gender OR sex} AND osteoarthritis" plus additional manual search of the included papers for pertinent references, yielding 212 references. Additional references were added and 343 were reviewed for appropriateness. RESULTS: Globally, women account for 60% of people with osteoarthritis, with a greater difference after age 40. The higher risk for women may be due to differences in joint anatomy, alignment, muscle strength, hormonal influences, obesity, and/or genetics. At the same radiographic severity, women have greater pain severity than men, which may be explained by biologically distinct pain pathways, differential activation of central pain pathways, differences in pain sensitivity, perception, reporting, and coping strategies. Women have greater limitations of physical function and performance than men independent of BMI, OA severity, injury history, and amount of weekly exercise. Women also have greater use of analgesic medications than men but less use of arthroplasty and poorer prognosis after surgical interventions. CONCLUSIONS: The recognition of sex differences in OA manifestations and management could guide tailoring of sex-specific treatment protocols, and analysis of sex as a biological variable in future research would enhance development of precision medicine.

Evaluation and Treatment of Knee Pain: A Review.

Importance: Approximately 5% of all primary care visits in adults are related to knee pain. Osteoarthritis (OA), patellofemoral pain, and meniscal tears are among the most common causes of knee pain. Observations: Knee OA, affecting an estimated 654 million people worldwide, is the most likely diagnosis of knee pain in patients aged 45 years or older who present with activity-related knee joint pain with no or less than 30 minutes of morning stiffness (95% sensitivity; 69% specificity). Patellofemoral pain typically affects people younger than 40 years who are physically active and has a lifetime prevalence of approximately 25%. The presence of anterior knee pain during a squat is approximately 91% sensitive and 50% specific for patellofemoral pain. Meniscal tears affect an estimated 12% of the adult population and can occur following acute trauma (eg, twisting injury) in people younger than 40 years. Alternatively, a meniscal tear may be a degenerative condition present in patients with knee OA who are aged 40 years or older. The McMurray test, consisting of concurrent knee rotation (internal or external to test lateral or medial meniscus, respectively) and extension (61% sensitivity; 84% specificity), and joint line tenderness (83% sensitivity; 83% specificity) assist diagnosis of meniscal tears. Radiographic imaging of all patients with possible knee OA is not recommended. First-line management of OA comprises exercise therapy, weight loss (if overweight), education, and self-management programs to empower patients to better manage their condition. Surgical referral for knee joint replacement can be considered for patients with end-stage OA (ie, no or minimal joint space with inability to cope with pain) after using all appropriate conservative options. For patellofemoral pain, hip and knee strengthening exercises in combination with foot orthoses or patellar taping are recommended, with no indication for surgery. Conservative management (exercise therapy for 4-6 weeks) is also appropriate for most meniscal tears. For severe traumatic (eg, bucket-handle) tears, consisting of displaced meniscal tissue, surgery is likely required. For degenerative meniscal tears, exercise therapy is first-line treatment; surgery is not indicated even in the presence of mechanical symptoms (eg, locking, catching). Conclusions and Relevance: Knee OA, patellofemoral pain, and meniscal tears are common causes of knee pain, can be diagnosed clinically, and can be associated with significant disability. First-line treatment for each condition consists of conservative management, with a focus on exercise, education, and self-management.

Inflammatory ultrasound features as prognostic factors of pain and functional outcomes following intra-articular platelet-rich plasma in knee osteoarthritis.

AIM: To explore inflammatory ultrasound predictors of improvements in pain and function over 2, 6, and 12 months following administration of intra-articular platelet-rich plasma (PRP) in knee osteoarthritis (OA). METHOD: Patients with painful mild-moderate radiographic knee OA from a subset of the RESTORE RCT underwent ultrasound assessment according to the standardized OMERACT scanning protocol to detect inflammatory features such as synovitis, synovial hypertrophy, and effusion with power Doppler. The study knee was treated with 3 once-weekly PRP injections obtained after centrifugation at 1500 g for 5 min. Numerical Rating Score (NRS), Intermittent and Constant Osteoarthritis Pain (ICOAP) questionnaire, and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) function sub-score were used to measure pain and functional severity. Separate linear regression models were performed to determine whether baseline ultrasound-detected features of inflammation predicted the improvement in pain and function following PRP injection in both unadjusted and adjusted models for confounders. RESULTS: Forty-four participants were included, with 25 (56.8%) being female. In an unadjusted model, higher OMERACT scores for inflammatory features such as global synovitis and/or effusion were significantly associated with greater improvement in all outcomes measured at 2 months but not at 6 and 12 months for pain measures. Only global synovitis showed significant association with functional improvement at 2 and 12 months. Similar findings were observed in the adjusted model. CONCLUSION: Ultrasound indices of knee inflammation predicted short-term improvements in pain severity and both short- and longer-term improvements in function following intra-articular PRP injection.

Sexual activity satisfaction in symptomatic hip osteoarthritis patients: A cross-sectional, national web-based study.

AIM: Despite high-interest rates in sex in people with hip osteoarthritis (OA), clinicians tend not to address sexual issues, especially in older adults. The objective of this study is to evaluate sexual activity and factors associated with sexual activity satisfaction in people with symptomatic hip OA. METHODS: A cross-sectional study was conducted among 252 participants with symptomatic hip OA in Australia. Quality of sex life was assessed using the online composite of sexual activities and positions questionnaires. A Poisson model with robust variance was used to calculate the prevalence ratio (PR). Factors that showed a univariate association with sexual satisfaction were then included in a multivariable model. PR with corresponding 95% confidence intervals (CI) are reported. RESULTS: Among the 282 participants registered on the study website, 252 met the inclusion criteria, and 60.3% (152/252) completed the sexual activity questionnaires. Hip OA interfered with sexual activity in 70.0% of the participants. High confidence in completing sexual activity (PR: 0.53, 95% CI: 0.36 to 0.77) was associated with an increased prevalence ratio of sexual satisfaction. High anxiety, depression or stress during sexual activity (PR: 1.33, 95% CI: 1.10 to 1.60) was associated with an increased prevalence ratio of sexual dissatisfaction after adjusting for hip pain level and perceived partner's orgasm. CONCLUSION: Although a large proportion of people with hip OA remain sexually active, a substantial proportion of persons are dissatisfied with their sexual activity. Hip OA interfered with sexual activity in most participants. Psychological factors were found to be associated with sexual activity satisfaction.

The effect of pentosan polysulfate sodium for improving dyslipidaemia and knee pain in people with knee osteoarthritis: A pilot study.

Objective: To evaluate the efficacy and safety of pentosan polysulfate sodium (PPS, Elmiron®) for dyslipidaemia and knee osteoarthritis (OA) related symptoms. Method: This was a single-arm, open-label, prospective, non-randomised pilot study. People with painful knee OA and a history of primary hypercholesterolemia were included. PPS was taken orally in a dosage of 10 â€‹mg/kg once every 4 days for 5 weeks for two cycles. There was 5 weeks of no medication between the cycles. The main outcomes included the change in lipidemia levels, the change in knee OA-related symptoms assessed by pain numerical rating scale (NRS) and Knee Osteoarthritis Outcome Score (KOOS), and knee MRI semi-quantitative score. The changes were analysed using paired t-tests. Results: 38 participants were included, with a mean age of 62.2 years. We found a statistically significant decrease in total cholesterol (from 6.23 â€‹± â€‹0.74 to 5.95 â€‹± â€‹0.77 â€‹mmol/L; P â€‹= â€‹0.01) and low-density lipoprotein (from 4.03 â€‹± â€‹0.61 to 3.82 â€‹± â€‹0.61 â€‹mmol/L; P â€‹= â€‹0.009) from baseline to week 16. Knee pain NRS was significantly reduced at weeks 6, 16 and 26 from 6.39 â€‹± â€‹1.33 to 4.18 â€‹± â€‹1.99, 3.63 â€‹± â€‹2.28 and 4.38 â€‹± â€‹2.55, respectively (P â€‹< â€‹0.001). However, there was no significant difference in terms of the primary outcome of triglyceride levels before and after treatment. The most common AEs were positive faecal occult blood tests, followed by headache and diarrhoea. Conclusion: The findings suggest that PPS has promising effects on improving dyslipidaemia and symptomatic pain relief in people with knee OA.

Efficacy, Safety, and Accuracy of Intra-articular Therapies for Hand Osteoarthritis: Current Evidence.

The lifetime risk of symptomatic hand osteoarthritis (OA) is 39.8%, with one in two women and one in four men developing the disease by age 85 years and no disease-modifying drug (DMOAD) available so far. Intra-articular (IA) therapy is one of the options commonly used for symptomatic alleviation of OA disease as it can circumvent systemic exposure and potential side effects of oral medications. The current narrative review focuses on the efficacy and safety profiles of the currently available IA agents in hand OA (thumb-base OA or interphalangeal OA) such as corticosteroids and hyaluronic acid (HA), as well as the efficacy and safety of IA investigational injectates in phase 2/3 clinical trials such as prolotherapy, platelet-rich plasma, stem cells, infliximab, interferon-? and botulinum toxin, based on the published randomized controlled trials on PubMed database. The limited published literature revealed the short-term symptomatic benefits of corticosteroids in interphalangeal OA while long-term data are lacking. Most of the short-term studies showed no significant difference between corticosteroids and hyaluronic acid in thumb-base OA, usually with a faster onset of pain relief in the corticosteroid group and a slower but greater (statistically insignificant) pain improvement in the HA group. The majority of studies in investigational agents were limited by small sample size, short-term follow-up, and presence of serious side effects. In addition, we reported higher accuracy rates of drug administrations under imaging guidance than landmark guidance (blind method), and then briefly describe challenges for the long-term efficacy and prospects of IA therapeutics.

Pain, function, and radiographic disease in trapeziometacarpal osteoarthritis.

INTRODUCTION: Trapeziometacarpal joint osteoarthritis (OA) produces significant functional impairment due to pain and loss of strength in both power and precision grips, but few studies have related radiographic scores to functional and pain-based measures. PURPOSE: To investigate the association between markers of radiographic disease and outcomes for symptomatic and functional disease. STUDY DESIGN: This study in an exploratory analysis of baseline data from the first 100 participants in a clinical trial evaluating the efficacy of combined conservative therapies for base of thumb OA (COMBO). METHODS: Functional Index for Hand Osteoarthritis (FIHOA) scores and Visual Analogue Scale (VAS) scores for pain were recorded for the index hand. Bilateral isometric grip and tip-pinch strength measurements were taken, as well as posteroanterior and Eaton stress-view hand radiographs. Generalized estimating equations (GEEs), univariate, and multivariate analyses were used according to whether the data were bilateral or unilateral. RESULTS: A total of 79 females and 21 males were included, with a median Kellgren-Lawrence (KL) grade of 3 in the index hand. Higher KL and Eaton grades were associated with lower grip strength in the GEE analysis (B-coefficients of -1.25 and -1.16, and P-values of .002 and .010, respectively). Higher KL grade was also associated with poorer function and higher pain levels in the multivariable analysis (B-coefficients of 1.029 and 3.681, and P-values of .021 and .047, respectively). Lower radial subluxation ratios were associated with lower grip strength in the GEE analysis, and higher pain scores in the multivariable analysis (B-coefficients of 2.06 and -42.1, and P-values of .006 and .031, respectively). Greater pain scores were also associated with poorer function (B-coefficient 0.082, P-value .001). CONCLUSION: More advanced radiographic trapeziometacarpal OA severity is associated with lower grip strength and poorer self-reported functional outcomes. Lower subluxation ratios were associated with higher pain scores and lower grip strength.

A narrative review of anti-obesity medications for obese patients with osteoarthritis.

INTRODUCTION: The prevalence of both obesity and osteoarthritis (OA) is increasing worldwide (twindemic), and the association between the two chronic diseases is also well established. AREAS COVERED: In this narrative review, we will briefly describe the double burdens of both diseases, the impact of weight loss or gain on OA incidence and structural progression and discuss the biomechanical and anti-inflammatory mechanisms mediating these effects. FDA-approved anti-obesity drugs are summarized in terms of their clinical efficacy and safety profile, and the completed or ongoing phase 2/3 clinical trials of such drugs in OA patients with obesity are examined. EXPERT OPINION: We will discuss the perspectives related to principles of prescription of anti-obesity drugs, the potential role of phenotype-guided approach, time to drug effects in clinical trials, sustainability of weight loss based on the real-world studies, the importance of concomitant therapies, such as dieting and exercises, and the role of weight loss on non-weight bearing OA joints. Although obesity is the major risk factor for OA pathogenesis and progression, and there are a variety of anti-obesity medications on the market, research on the use of these disease-modifying drugs in OA (DMOAD) is still sparse.

Associations of + 138 Ins/del A and + 5665 G/T polymorphisms of endothelin-1 gene with hypertension in Burmese people in Magway, Myanmar.

BACKGROUND: Hypertension is one of the major public health problems worldwide, and is one of the recognized causes of premature deaths every year in the world. The purpose of this study was to investigate the associations between the + 138 insertion/deletion of adenine (Ins/del A) and + 5665 guanine-to-thymine (G/T) polymorphisms of the endothelin-1 gene and hypertension in the residents of Magway Township, Myanmar. METHODS: This study was a cross-sectional comparative study including 60 hypertensive patients and 60 control subjects in Magway Township, Myanmar. The inclusion criterion for hypertension was blood pressure ≥ 140/90 mmHg or previous diagnosis by a physician as hypertension and/or taking antihypertensive drugs. The control group had blood pressure < 140/90 mmHg and no previous diagnosis of hypertension. The genotyping was done by polymerase chain reaction and restriction fragment length polymorphism method. RESULTS: In this study, the genotype distribution of the + 138 Ins/del A variant was significantly different between hypertensive patients and the control group, especially in the 3A4A genotype (odds ratio [OR], 2.451; 95% confidence interval [CI], 1.138-5.280; P = 0.022). Adenine insertion genotypes (3A4A and 4A4A) were significantly associated with hypertension in the dominant model (OR, 2.494; 95% CI, 1.179-5.276; P = 0.017). In addition, there was a significant association between the 4A allele and hypertension (OR, 1.771; 95% CI, 1.026-3.056; P = 0.040). The genotype and allelic distributions of the + 5665 G/T polymorphism were not significantly different between the hypertensive patients and the control group (P > 0.05). In this study, there was no significant association between the genotype and allele frequency, and hypertension (P > 0.05). The linkage disequilibrium was weak between the + 138 Ins/del A and + 5665 G/T loci (D' = 0.108, r2 = 0.009). CONCLUSIONS: This study provides evidence that the + 138 Ins/del A rather than + 5665 G/T polymorphism is associated with hypertension in Burmese people.

Repurposed and investigational disease-modifying drugs in osteoarthritis (DMOADs).

In spite of a major public health burden with increasing prevalence, current osteoarthritis (OA) management is largely palliative with an unmet need for effective treatment. Both industry and academic researchers have invested a vast amount of time and financial expense to discover the first diseasing-modifying osteoarthritis drugs (DMOADs), with no regulatory success so far. In this narrative review, we discuss repurposed drugs as well as investigational agents which have progressed into phase II and III clinical trials based on three principal endotypes: bone-driven, synovitis-driven and cartilage-driven. Then, we will briefly describe the recent failures and lessons learned, promising findings from predefined post hoc analyses and insights gained, novel methodologies to enhance future success and steps underway to overcome regulatory hurdles.

Prospects of Disease-Modifying Osteoarthritis Drugs.

Osteoarthritis (OA) causes a massive disease burden with a global prevalence of nearly 23% in 2020 and an unmet need for adequate treatment, given a lack of disease-modifying drugs (DMOADs). The author reviews the prospects of active DMOAD candidates in the phase 2/3 clinical trials of drug development pipeline based on key OA pathogenetic mechanisms directed to inflammation-driven, bone-driven, and cartilage-driven endotypes. The challenges and possible research opportunities are stated in terms of the formulation of a research question known as the PICO approach: (1) population, (2) interventions, (3) comparison or placebo, and (4) outcomes.

Associations between radiographic features, clinical features and ultrasound of thumb-base osteoarthritis: A secondary analysis of the COMBO study.

AIM: To investigate the associations of ultrasound and radiographic features of thumb-base osteoarthritis (OA) with thumb-base pain and hand function at baseline and 12 weeks. METHOD: Data from a randomized controlled trial conducted in participants with symptomatic radiographic thumb-base OA were analyzed. Participants who finished follow up were included in this secondary analysis. Pain and hand function were assessed using self-reported measures. All participants underwent ultrasound examinations for synovitis, power Doppler signal (PDS), and osteophytes, and underwent radiography for osteophytes, joint space narrowing (JSN), and subchondral bone sclerosis at baseline. Hand pain and function were reassessed after the 12-week follow up. The associations of ultrasound and radiographic findings with clinical features were further evaluated, using linear regression analyses, after adjustment for relevant confounding factors. RESULTS: A total of 166 participants (average age 66.2 years; 76.5% female) were included. At baseline, radiographic JSN and subchondral bone sclerosis were associated with hand function. There was a significant association between ultrasound-detected PDS and patient's global assessment (PGA) at baseline. Baseline radiographic JSN was significantly associated with the changes in stiffness and PGA from baseline to 12 weeks. There was no association between ultrasound features and changes in the clinical outcomes over 12 weeks. CONCLUSION: This study indicates that radiographic features significantly correlate with hand function, and ultrasound PDS is closely related to the PGA at baseline in thumb-base OA. Radiographic JSN may be a predictor for stiffness and PGA in thumb-base OA.

Reliability and Convergent Construct Validity of Quantitative Ultrasound for Synovitis, Meniscal Extrusion, and Osteophyte in Knee Osteoarthritis With MRI.

AIMS: To determine: 1) inter-rater reliability of quantitative measurements of ultrasound-detected synovitis, meniscal extrusion, and osteophytes; and 2) construct (convergent) validity via correlations and absolute agreements between ultrasound- and gold-standard magnetic resonance imaging (MRI)-outcomes in knee osteoarthritis. METHODS: Dynamic ultrasound images for supra-patellar synovitis, meniscal extrusion, and osteophytes were acquired and quantified by a physician operator, musculoskeletal ultrasonographer, and medical student independently. On the same day, 3T MRI images were acquired. Effusion-synovitis, meniscal extrusion, and osteophytes were quantified on sagittal or coronal proton-density-weighted fat-suppressed noncontrast TSE sequences, respectively. Intra-class correlation coefficients (ICCs), Pearson's correlations (r), and Bland-Altman plots were used to analyze inter-rater reliability, and correlations, and agreements between the two imaging modalities. RESULTS: Eighty-nine participants [48 females (53.9%)] with mean (standard deviation) age of 61.5 ± 6.9 years were included. The inter-rater reliability was excellent for osteophytes (ICC range = 0.90-0.96), meniscal extrusion (ICC range = 0.90-0.93), and synovitis (ICC range = 0.86-0.88). The correlations between ultrasound pathologies and their MRI counterparts were very strong (ICC range = 0.85-0.98) except for lateral meniscal extrusion [0.66 (95% CI, 0.52-0.76)]. Bland-Altman plots showed 0.01, 0.05, 0.10, 0.53, and 0.60 mm larger size in ultrasound medial tibial and medial femoral osteophytes, medial meniscal extrusions, synovitis, and lateral meniscal extrusions with 95% limits of agreements [±0.39, ±0.44, ±0.85, ±0.70, and ±0.90 (SDs)] than MRI measures, respectively. The lines of equality were within 95% CI of the mean differences (bias) only for medial osteophytes and medial meniscal extrusion. CONCLUSION: The quantitative assessment of synovitis, meniscal extrusion, and osteophytes generally showed excellent inter-rater reliability and strong correlations with MRI-based measurements. Absolute agreement was strong for medial tibiofemoral pathologies.

Efficacy and cost-effectiveness of Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis: protocol for a randomised placebo-controlled trial (the SCUlpTOR trial).

INTRODUCTION: Knee osteoarthritis (KOA) is a highly prevalent disabling joint disease. Intra-articular stem cell therapy is increasingly being used for treating KOA with little high-quality evidence to support its use. The aim of this study is to investigate the efficacy, safety and cost-effectiveness of allogeneic mesenchymal stem cells (Cymerus MSCs) for treating symptomatic tibiofemoral KOA and improving knee structure over 24 months. METHODS AND ANALYSIS: The Stem Cell injections for symptomatic relief and strUctural improvement in people with Tibiofemoral knee OsteoaRthritis study is a phase III, multi-centre, parallel, superiority, randomised, double-blind, placebo-controlled trial, which will be conducted in Sydney and Hobart, Australia. 440 participants (220 per arm) aged over 40 years with painful KOA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) with medial minimum joint space width between 1 and 4 mm in the study knee will be recruited from the community and randomly allocated to receive either intra-articular MSCs or saline at baseline, week 3 and week 52. The coprimary outcomes will be the proportion of participants achieving patient-acceptable symptom state for knee pain at 24 months and quantitative central medial femorotibial compartment cartilage thickness change from baseline to 24 months. Main secondary outcomes include change in knee pain, Patient Global Assessment, physical function, quality of life and other structural changes. Additional data for cost-effectiveness analysis will also be recorded. Adverse events will be monitored throughout the study. The primary analysis will be conducted using modified intention-to-treat. ETHICS AND DISSEMINATION: This protocol has been approved by The University of Sydney (USYD) Human Research Ethics Committee (HREC) #: 2020/119 and The University of Tasmania (UTAS) HREC #: H0021868. All participants will be required to provide informed consent. Dissemination will occur through conferences, social media, and scientific publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trials Registry (ACTRN12620000870954); U1111-1234-4897.

Nerve Growth Factor (NGF) Inhibitors and Related Agents for Chronic Musculoskeletal Pain: A Comprehensive Review.

Musculoskeletal pain such as osteoarthritis (OA) and low back pain (LBP) are very common and contribute to enormous burden and societal costs, despite dramatic therapeutic advances over recent decades. Novel approaches and targeted therapies are required to satisfy the urgent unmet medical need of musculoskeletal pain relief in both conditions. Nerve growth factor (NGF) inhibitors have utilized novel mechanisms different from conventional drugs, which have a variety of gastrointestinal, cardiac, or renal adverse effects. Several phase 2/3 studies have been accomplished for these drugs, such as tanezumab, fasinumab, and tyrosine receptor kinase A (TrkA) inhibitors. We searched the literature using the PubMed database and clinical trials using ClinicalTrials.gov to identify original papers, meta-analyses as well as ongoing clinical trials assessing the efficacy and safety profile of these drugs. In this narrative review, we briefly overview the disease burden of musculoskeletal pain, the role of NGF signaling and its receptors in the genesis of pain, and the mechanisms of action of inhibitors of NGF signaling and downstream pathways, and then discuss the efficacy and safety of each investigational drug in OA and LBP. Finally, we briefly review two serious adverse effects of NGF inhibitors, namely rapidly progressive OA and sympathetic system effects, and conclude with possible barriers and potential research directions to overcome these.

Effect of Intra-articular Platelet-Rich Plasma vs Placebo Injection on Pain and Medial Tibial Cartilage Volume in Patients With Knee Osteoarthritis: The RESTORE Randomized Clinical Trial.

Importance: Most clinical guidelines do not recommend platelet-rich plasma (PRP) for knee osteoarthritis (OA) because of lack of high-quality evidence on efficacy for symptoms and joint structure, but the guidelines emphasize the need for rigorous studies. Despite this, use of PRP in knee OA is increasing. Objective: To evaluate the effects of intra-articular PRP injections on symptoms and joint structure in patients with symptomatic mild to moderate radiographic medial knee OA. Design, Setting, and Participants: This randomized, 2-group, placebo-controlled, participant-, injector-, and assessor-blinded clinical trial enrolled community-based participants (n = 288) aged 50 years or older with symptomatic medial knee OA (Kellgren and Lawrence grade 2 or 3) in Sydney and Melbourne, Australia, from August 24, 2017, to July 5, 2019. The 12-month follow-up was completed on July 22, 2020. Interventions: Interventions involved 3 intra-articular injections at weekly intervals of either leukocyte-poor PRP using a commercially available product (n = 144 participants) or saline placebo (n = 144 participants). Main Outcomes and Measures: The 2 primary outcomes were 12-month change in overall average knee pain scores (11-point scale; range, 0-10, with higher scores indicating worse pain; minimum clinically important difference of 1.8) and percentage change in medial tibial cartilage volume as assessed by magnetic resonance imaging (MRI). Thirty-one secondary outcomes (25 symptom related and 6 MRI assessed; minimum clinically important difference not known) evaluated pain, function, quality of life, global change, and joint structures at 2-month and/or 12-month follow-up. Results: Among 288 patients who were randomized (mean age, 61.9 [SD, 6.5] years; 169 [59%] women), 269 (93%) completed the trial. In both groups, 140 participants (97%) received all 3 injections. After 12 months, treatment with PRP vs placebo injection resulted in a mean change in knee pain scores of -2.1 vs -1.8 points, respectively (difference, -0.4 [95% CI, -0.9 to 0.2] points; P = .17). The mean change in medial tibial cartilage volume was -1.4% vs -1.2%, respectively (difference, -0.2% [95% CI, -1.9% to 1.5%]; P = .81). Of 31 prespecified secondary outcomes, 29 showed no significant between-group differences. Conclusions and Relevance: Among patients with symptomatic mild to moderate radiographic knee OA, intra-articular injection of PRP, compared with injection of saline placebo, did not result in a significant difference in symptoms or joint structure at 12 months. These findings do not support use of PRP for the management of knee OA. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12617000853347.