Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial.

OBJECTIVE: To compare the efficacy of an exercise and education programme with open-label placebo given as intra-articular injections of inert saline on pain and function in individuals with knee osteoarthritis (OA). METHODS: In this open-label, randomised controlled trial, we recruited adults aged ≥50 years with symptomatic and radiographically confirmed knee OA in Denmark. Participants were randomised 1:1 to undergo an 8-week exercise and education programme or four intra-articular saline injections over 8 weeks. Primary outcome was change from baseline to week 9 in the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire pain subscale (range 0 (worst)-100 (best)). Prespecified equivalence margins of ±8 KOOS pain points were chosen for the demonstration of comparable efficacy. Key secondary outcomes were the KOOS function and quality of life subscales, and patients' global assessment of disease impact. RESULTS: 206 adults were randomly assigned: 102 to exercise and education and 104 to intra-articular saline injections. For the primary outcome, the least squares mean changes in KOOS pain were 10.0 for exercise and education and 7.3 for saline injections (difference 2.7 points, 95% CI -0.6 to 6.0; test for equivalence p=0.0008). All group differences in the key secondary outcomes respected the predefined equivalence margins. Adverse events and serious adverse events were similar in the two groups. CONCLUSION: In individuals with knee OA, an 8-week exercise and education programme provided efficacy for symptomatic and functional improvements equivalent to that of four open-label intra-articular saline injections over 8 weeks. TRIAL REGISTRATION NUMBER: NCT03843931.

OLT1177, a ß-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation.

Activation of the NLRP3 inflammasome induces maturation of IL-1ß and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active ß-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1ß and IL-18 release following canonical and noncanonical NLRP3 inflammasome activation. The molecule showed no effect on the NLRC4 and AIM2 inflammasomes, suggesting specificity for NLRP3. In LPS-stimulated human blood-derived macrophages, OLT1177 decreased IL-1ß levels by 60% and IL-18 by 70% at concentrations 100-fold lower in vitro than plasma concentrations safely reached in humans. OLT1177 also reduced IL-1ß release and caspase-1 activity in freshly obtained human blood neutrophils. In monocytes isolated from patients with cryopyrin-associated periodic syndrome (CAPS), OLT1177 inhibited LPS-induced IL-1ß release by 84% and 36%. Immunoprecipitation and FRET analysis demonstrated that OLT1177 prevented NLRP3-ASC, as well as NLRP3-caspase-1 interaction, thus inhibiting NLRP3 inflammasome oligomerization. In a cell-free assay, OLT1177 reduced ATPase activity of recombinant NLRP3, suggesting direct targeting of NLRP3. Mechanistically, OLT1177 did not affect potassium efflux, gene expression, or synthesis of the IL-1ß precursor. Steady-state levels of phosphorylated NF-κB and IkB kinase were significantly lowered in spleen cells from OLT1177-treated mice. We observed reduced IL-1ß content in tissue homogenates, limited oxidative stress, and increased muscle oxidative metabolism in OLT1177-treated mice challenged with LPS. Healthy humans receiving 1,000 mg of OLT1177 daily for 8 d exhibited neither adverse effects nor biochemical or hematological changes.

Obesity Impacts Swelling of Ankle and Foot Joints in Early Rheumatoid Arthritis Patients.

OBJECTIVE: The evaluation of disease activity in obese rheumatoid arthritis (RA) patients presents challenges particularly in the clinical assessment of swollen joints. This study examines the effect of obesity on the American College of Rheumatology (ACR) core set measures used in assessing RA disease activity with specific focus on the swollen joint count (SJC). METHODS: We examined a cross-sectional cohort of 323 early seropositive RA patients (symptom duration ≤15 months). Patients were biologic-naive with equal to or more than 6/44 SJC and equal to or more than 9/44 tender joint count. The ACR core set measures, components of Disease Activity Score (DAS) 44/erythrocyte sedimentation rate (ESR), DAS28/ESR4 item, Clinical Disease Activity Index (CDAI), and body mass index (BMI) were collected. Disease activity measures were compared between BMI categories. Multivariable linear regression models assessed the relationship between high BMI (≥30 kg/m) and lower-extremity (LE) SJC and SJC44 while accounting for other ACR measures. RESULTS: Disease Activity Score 44/ESR4 item, Health Assessment Questionnaire Disability Index, physician global, and SJC44 differed across BMI categories (p < 0.05). Of the SJC44, metacarpophalangeal joints and LE joints (knees, ankles, metatarsophalangeal joints) were associated with increased swelling in all BMI groups (P < 0.05). Obesity was significantly associated with LE SJC after adjusting for ACR core set measures. CONCLUSIONS: There is a direct association between increased BMI and increased swelling of LE joints in RA patients. Increases in DAS44-measured disease activity are higher in obese RA patients because of increased LE swollen joints. Disease Activity Score 28 and Clinical Disease Activity Index, which emphasize upper-extremity joint assessment, are not significantly influenced by obesity.

Hyaluronic Acid Injections in Medicare Knee Osteoarthritis Patients Are Associated With Longer Time to Knee Arthroplasty.

BACKGROUND: Few nonoperative treatment options for knee osteoarthritis (OA) are available, but there is ongoing debate about the effectiveness of intra-articular (IA) hyaluronic acid (HA) injections. We investigated whether the formulation of IA HA, or its combined use with IA corticosteroid (CS), may be contributing to some of the reported variation in clinical outcomes. METHODS: The 5% Part B Medicare data (2005-2012) were used to identify knee OA patients who underwent knee arthroplasty (KA). The time from diagnosis of OA to KA was compared between patients with (HA) and without (no HA) IA HA use, using quantile regression with propensity score adjustment. These were further stratified by type of IA HA. Patient factors associated with time to KA were also assessed using Cox regression. RESULTS: The "HA" cohort was associated with a longer time to KA of 8.7 months (95% confidence interval: 8.3-9.1 months; P < .001) compared with the "no HA" cohort, with extended time to KA in the bioengineered Euflexxa IA HA cohort. Patient factors associated with longer time to KA included women, younger patients, minority patients, patients with fewer comorbidities, and IA CS injection use. Patients with both IA HA and IA CS had an additional 6.3 months (95% confidence interval: 5.5-7.0 months; P < .001) to KA over those with only IA HA. CONCLUSION: In a large cohort of elderly patients undergoing KA, there was a significant longer time from diagnosis of OA to KA in those receiving IA HA. It is unclear if the extended time may lead to less KA utilization.

RS3PE: Clinical and Research Development.

Remitting seronegative symmetrical synovitis with pitting edema or RS3PE is a rare elderly-onset rheumatic syndrome. Although there are overlapping clinical manifestations between RS3PE, elderly-onset rheumatoid arthritis, and polymyalgia rheumatica, RS3PE has distinct characteristics. RS3PE can be associated with neoplasia and various rheumatic conditions, suggesting that it may be heterogeneous, and is considered as a paraneoplastic rheumatic disease. The pathogenesis of RS3PE may involve vascular endothelial growth factor and infection in RS3PE based upon limited data. Patients with RS3PE without concomitant malignancy respond well to small doses of glucocorticoids and carry good prognosis.

Indomethacin submicron particle capsules provide effective pain relief in patients with acute pain: a phase 3 study.

Although frequently prescribed to relieve acute pain in patients, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with dose-related gastrointestinal, cardiovascular, and renal complications. Investigational, submicron particle NSAIDs are being developed that could provide effective pain relief at lower doses than currently available oral NSAIDs. This is the first phase 3 study evaluating the analgesic efficacy and safety of lower-dose indomethacin submicron particle capsules in patients following elective surgery. This multicenter, double-blind study enrolled patients aged 18 to 68 years who underwent bunionectomy under regional anesthesia. Patients with a pain intensity rating of ≥40 mm on a 100-mm Visual Analog Scale were randomized to receive indomethacin submicron particle capsules (40 mg 3 times daily [TID], 40 mg twice daily [BID], or 20 mg TID), celecoxib (400 mg loading dose, then 200 mg BID), or placebo. The primary efficacy parameter was the overall (summed) pain intensity difference measured by a Visual Analog Scale during a period of 48 hours. Scheduled assessments measured secondary efficacy parameters such as patient pain intensity differences. Indomethacin submicron particle capsules 40 mg 3 times daily (509.6 ± 91.9 overall [summed] pain intensity difference), 40 mg twice daily (328.0 ± 92.9 overall [summed] pain intensity difference), and 20 mg 3 times daily (380.5 ± 92.9 overall [summed] pain intensity difference) reduced pain intensity from 0 to 48 hours (P ≤ 0.046 for all 3 groups) compared with placebo (67.8 ± 91.4 overall [summed] pain intensity difference). There was some evidence of patient analgesia for celecoxib (279.4 ± 91.9 overall [summed] pain intensity difference; P = 0.103). Some evidence of pain control was observed in patients as early as 2 hours following administration of indomethacin submicron particle capsules and was sustained throughout the treatment period. Indomethacin submicron particle capsules were generally well tolerated by patients. These results suggest that lower-dose indomethacin submicron particle capsules are a potentially promising treatment option for patients with acute pain.

Prognostic value of illness perception on changes in knee pain among elderly individuals: Two-year results from the Frederiksberg Cohort study.

Objective: To investigate the prognostic value of illness perception (IP) on knee pain, quality of life (QoL) and functional level in elderly individuals reporting knee pain. Design: A prospective cohort study of 1552 elderly with knee pain comparing two previously established clusters based on the Brief Illness Perception questionnaire. Cluster 1 ("Concerned optimists" [hypothesized unfavorable profile]; n â€‹= â€‹642) perceived their knee pain as a greater threat to them than Cluster 2 ("Unconcerned confident" [hypothesized favorable profile]; n â€‹= â€‹910). Primary outcome was the change from baseline to year 2 in the KOOS Pain subscale. Secondary outcomes were changes from baseline in quality of life (EuroQol-5 Domain and EQ VAS) and in the KOOS subscales Symptom, Activities of Daily Living, Knee-related QoL and Sports and recreation. Analyses were done on the original Intention-To-Survey (ITS) population, using repeated measures mixed linear models. Results: Among the ITS population, 841 (54%) responded to the 2-year survey. There was a statistically significant but clinically irrelevant cluster difference in the 2-year change from baseline in KOOS pain (mean difference: 6.0 KOOS points [95% CI: 7.3 to -4.7]) explained by a minor improvement in Cluster 1: (6.2 points) and no changes in Cluster 2: (0.2 points). Comparable results were found across the secondary outcomes. Clinically irrelevant cluster changes in IP were seen. Conclusion: In a cohort of people with knee pain, IP phenotype (i.e., Clusters) were of no prognostic value for the 2-year changes in pain, function, and QoL. Targeting IP may not be relevant in this patient population. Trial registration number and date of registration: The Frederiksberg Cohort study was pre-registered at clinicaltrials.gov (NCT03472300) on March 21, 2018.

Comparative effectiveness of pharmacological interventions for hand osteoarthritis: a systematic review and network meta-analysis of randomised trials.

OBJECTIVE: To explore the comparative effectiveness of pharmacological interventions for hand osteoarthritis (OA). METHODS: We systematically searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials from inception until 26 December 2021, for randomised trials of pharmacological interventions for people with hand OA. Two reviewers independently extracted study data and assessed the risk of bias. We calculated the effect sizes for pain (standardised mean differences) using Bayesian random effects models for network meta-analysis (NMA) and pairwise meta-analysis. Based on a pre-specified protocol, we prospectively registered the study at PROSPERO, CRD42021215393. RESULTS: We included 72 trials with 7609 participants. 65 trials (n=5957) were eligible for the quantitative synthesis, investigating 29 pharmacological interventions. Oral non-steroidal anti-inflammatory drugs (NSAIDs) and oral glucocorticoids' NMA effect sizes were -0.18 (95% credible interval -0.36 to 0.02) and -0.54 (-0.83 to -0.24), respectively, compared with placebo, and the result was consistent when limiting evidence to the pairwise meta-analysis of trials without high risk of bias. Intra-articular hyaluronate, intra-articular glucocorticoids, hydroxychloroquine, and topical NSAIDs' NMA effect sizes were 0.22 (-0.08 to 0.51), 0.25 (0.00 to 0.51), -0.01 (-0.19 to 0.18), and -0.14 (-0.33 to 0.08), respectively, compared with placebo. Oral NSAIDs were inferior to oral glucocorticoids with an NMA effect size of 0.36 (0.01 to 0.72). No intervention was superior to placebo when stratifying for thumb and finger OA. CONCLUSION: Oral NSAIDs and glucocorticoids are apparently effective pharmacological interventions in hand OA. Intra-articular therapies and topical NSAIDs were not superior to placebo.

Colchicine twice a day for hand osteoarthritis (COLOR): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Colchicine has been suggested for osteoarthritis treatment, but evidence is contradictory. We aimed to investigate colchicine's efficacy and safety compared with placebo in people with hand osteoarthritis. METHODS: In this single-centre, double-blind, randomised, placebo-controlled trial we recruited adults with symptomatic hand osteoarthritis and finger pain of at least 40 mm on a 100 mm visual analogue scale from an outpatient clinic in Denmark. The hand with the most severe finger pain at inclusion was the target hand. Participants were randomly assigned (1:1) to 0·5 mg colchicine or placebo taken orally twice a day for 12 weeks, stratified by BMI (≥30 kg/m2), sex, and age (≥75 years). Participants, outcome assessors, and data analysts were masked to treatment allocation. The primary endpoint was change from baseline to week 12 in target hand finger pain, assessed on a 100 mm visual analogue scale with a pre-specified minimal clinically important difference of 15 mm, in the intention-to-treat population. Safety was assessed at week 12 in the intention-to-treat population. The study was registered with ClinicalTrials.gov, NCT04601883, and with EudraCT, 2020-002803-20. FINDINGS: Between Jan 15, 2021, and March 3, 2022, 186 people were screened for eligibility, and 100 were randomly assigned to receive colchicine (n=50) or placebo (n=50). Participants had a mean age of 70·9 (SD 7·5) years, 69 (69%) of 100 were women and 31 (31%) were men. All participants completed the study. The mean change from baseline to week 12 in finger pain were -13·9 mm (SE 2·8) in the colchicine group and -13·5 mm (2·8) in the placebo group, with a between-group difference (colchicine vs placebo) of -0·4 mm (95% CI -7·6 to 6·7; p=0·90). In the colchicine group, there were 76 adverse events in 36 (72%) of 50 participants and one serious adverse advent (migraine attack leading to hospital admission). In the placebo group, there were 42 adverse events in 22 (44%) of 50 participants and two serious adverse events (cholecystitis and elevated alanine aminotransferase concentrations, in the same patient). INTERPRETATION: In people with painful hand osteoarthritis, treatment with 0·5 mg of colchicine twice day for 12 weeks did not effectively relieve pain, and treatment with colchicine was associated with more adverse events. FUNDING: The Oak Foundation, IMK Almene Fond, Minister Erna Hamilton's Scholarship for Science and Art, AP Moller and Wife Chastine McKinney Moller's Foundation for Medical Science Advancement, The Danish Medical Association, the Velux Foundation, Aase and Ejnar Danielsen's Foundation, and Director Emil C Hertz and Wife Inger Hertz's foundation.

Systemic lupus erythematosus with Sjögren syndrome compared to systemic lupus erythematosus alone: a meta-analysis.

OBJECTIVES: This study aimed to compare the difference of the clinical and laboratory features of the patients between the combined systemic lupus erythematosus (SLE) and Sjögren syndrome (SLE-SS) and SLE only. MATERIALS AND METHODS: A systematic literature search was performed to identify the articles as to SLE with SS between 1970 and May 2011. The demographics, pertinent clinical, and laboratory data were extracted from 6 publications, and a meta-analysis was performed. The pooled odds ratios and 95% confidence interval were computed for the variability of these parameters between SLE-SS and SLE. RESULTS: A total of 6 studies were included, consisting of 2489 patients with SLE and 444 with SLE-SS, and the estimated prevalence of the latter was 17.8%. Patients with SLE-SS were older and more often had associated oral ulcers and arthritis. In contrast, proteinuria (odds ratio = 1.77; 95% confidence interval, 1.39-2.25; P < 0.0001) was more common in SLE alone than SLE-SS, and central nervous system involvement tended to be more common. Anti-double-stranded DNA antibodies were equally prevalent in both groups. Anti-SSA/Ro and anti-SSB/La antibodies were more frequent, and anti-Sm and anti-cardiolipin antibodies were less prevalent in SLE-SS than SLE alone. CONCLUSIONS: There are significant variances in certain clinical and laboratory aspects between SLE-SS and SLE. This combined disease of SLE-SS has distinct features with relatively less major internal organ involvement but has more specific autoantibody profile and favorable clinical outcome.

Pharmacologic treatment of knee osteoarthritis in athletic women.

There is a greater incidence of anterior cruciate ligament tears due to noncontact sports injuries in women compared with men. Anterior cruciate ligament tears are associated with accelerated development of knee osteoarthritis (OA), which is also more prevalent in women than in men. This article considers therapeutic modalities that are best suited for athletic women with knee OA. Clinical data on the safety and efficacy of pharmacotherapies for knee OA, including acetaminophen, oral nonsteroidal anti-inflammatory drugs (NSAIDs), and topical NSAIDs, are discussed, with attention paid to special considerations for women who participate in athletic activity. Adverse events associated with the use of acetaminophen and oral NSAIDs place potential limits on the dose and duration of therapy and may be of greater concern in female athletes than in other patient groups. Topical NSAIDs, which effect relief through the same mechanism of action as oral NSAIDs, produce dramatically lower systemic NSAID exposure compared with oral NSAIDs and are associated with a lower incidence of systemic adverse events. These findings, along with additional future studies, may have particular relevance to the choice of the most effective treatment options for athletic women with OA of the knee.

Factors Associated with Knee Arthroplasty in a Knee Osteoarthritis Patient Cohort Treated with Intra-articular Injections of Hylan G-F 20.

Hylan G-F 20 viscosupplementation can be used to treat knee osteoarthritis pain. This study evaluated time to knee arthroplasty (KA), KA risk factors, and health care resource utilization in patients aged ≥18 years with claims in the Optum Clinformatics Data Mart database (2006-2016) for knee osteoarthritis treated with at least one course of hylan G-F 20. Kaplan-Meier analysis estimated KA risk from osteoarthritis diagnosis and first hylan G-F 20 treatment. KA risk factors were determined using multivariate Cox regression. Among 62,033 patients treated with hylan G-F 20 and/or hylan G-F 20 single intra-articular injection, 60 to 64% did not undergo KA 8 years following first injection. KA risk factors from time of osteoarthritis diagnosis and first hylan G-F 20 treatment were similar: increased age, fewer comorbidities, fewer hylan G-F 20 treatments, female sex, and no ultrasound/fluoroscopy for injection guidance. Patients who underwent KA versus those who did not had more office visits and claims for opioids, nonsteroidal anti-inflammatory drugs, and physical therapy. Patients less likely to undergo KA were younger (<40 years), had more comorbidities, received more courses of hylan G-F 20, were males, or received ultrasound/fluoroscopic injection guidance. Patients who did not receive KA versus those who did used fewer health care resources.

Safety of Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized Trials Involving More than 8,000 Patients.

OBJECTIVE: The objective of this systematic review and meta-analysis was to report the safety of intra-articular hyaluronic acid (IAHA) in patients with symptomatic knee osteoarthritis (OA). METHODS: We identified randomized controlled trials reporting the safety of IAHA versus IA saline in adults with symptomatic knee OA. Main safety outcomes were adverse events (AEs), local AEs, serious adverse events (SAEs), study withdrawals, and AE-related study withdrawals. RESULTS: A total of 35 randomized controlled trials with 38 group comparisons comprising 8,078 unique patients (IAHA: 4,295, IA saline: 3,783) were included in the meta-analysis. Comparing IAHA with IA saline over a median of 6 months follow-up, there were no differences in the risk of AEs (42.4% vs. 39.7%, risk ratio [RR] = 1.01, 95% CI = 0.96-1.07, P = 0.61), SAEs (1.8% vs. 1.2%, RR = 1.44, 95% CI = 0.91-2.26, P=0.12), study withdrawals (12.3% vs. 12.7%, RR = 0.99, 95% CI = 0.87-1.12, P = 0.83), or AE-related study withdrawals (2.7% vs. 2.1%, RR = 1.37, 95% CI = 0.97-1.93, P = 0.08). Local AEs, all of which were nonserious, were more common with IAHA vs. IA saline (14.5% vs. 11.7%, RR = 1.21, 95% CI = 1.07-1.36, P = 0.003) and typically resolved within days. CONCLUSION: IAHA was shown to be safe for use in patients with symptomatic knee OA. Compared with IA saline, IAHA is associated with an increased risk of nonserious, transient local reactions. There was no evidence to suggest any additional safety risks of IAHA.

Severe Acute Localized Reactions Following Intra-Articular Hyaluronic Acid Injections in Knee Osteoarthritis.

OBJECTIVE: Concerns have been raised about severe acute localized reactions (SALR) following intra-articular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA). We compared surrogate SALR measures between hylan G-F 20 and non-hylan G-F 20 HA patients and evaluated corresponding SALR risk factors for hylan G-F 20 patients. DESIGN: Knee OA patients were identified from the Optum Clinformatics dataset (January 2006 to June 2016), stratified into hylan G-F 20 and non-hylan G-F 20 HA users. Occurrences of surrogate SALR measures including inflammation/infection, intra-articular corticosteroid (CS) injections, arthrocentesis/aspiration, and office visits were evaluated within 3 days of HA use. Risk factors were evaluated using logistic regression. RESULTS: The cohort involved 748,428 HA patients (23.2% in the hylan G-F 20 group). Inflammation/infection rate was 0.001% for hylan G-F 20 and 0.002% for non-hylan G-F 20 HA groups. Risk of CS injection (any diagnosis) was greater for hylan G-F 20 patients by 28% (P < 0.001). Combined rates of CS injection and arthrocentesis/aspiration (any diagnosis) were comparable for both groups (hylan G-F 20, 2.2%; non-hylan G-F 20 HA, 2.6%). The risk of any visit or studied responses was lower for the hylan G-F 20 cohort by 12% (P < 0.001). Clinical characteristics, such as CS injections within 1 week before HA and fluoroscopic imaging, were associated with the outcomes. CONCLUSIONS: The diagnosis of inflammations or infections within 3 days of the HA injection was extremely rare. The overall risk of surrogate SALR measures was similar for hylan G-F 20 and non-hylan G-F 20 HA patients.

Estimating the Prevalence of Knee Pain and the Association between Illness Perception Profiles and Self-Management Strategies in the Frederiksberg Cohort of Elderly Individuals with Knee Pain: A Cross-Sectional Study.

Knee pain is an early sign of later incident radiographic knee osteoarthritis (OA). However, the prevalence of knee pain in the general population is unknown. Additionally, it is unknown how people with knee pain choose to self-manage the condition and if the perception of the illness affects these choices. In this study, 9086 citizens between 60-69 years old in the municipality of Frederiksberg, Copenhagen, Denmark, were surveyed, of which 4292 responded. The prevalence of knee pain was estimated, and associations between illness perceptions (brief illness perception questionnaire [B-IPQ]), self-management strategies, and knee symptoms were assessed. The prevalence of knee pain was 21.4% of which 40.5% reported to use no self-management strategies (non-users). These non-users perceived their knee pain as less threatening and reported less severe symptoms than users of self-management strategies. Further, we found that a more positive illness perception was associated with less severe knee symptoms. In conclusion, among Danes aged 60-69 years, the knee pain prevalence is 21.4%, of which 40.5% use no treatment and perceive the condition as non-threatening. These non-users with knee pain represent a subpopulation being at increased risk of developing knee OA later in life, and there is a potential preventive gain in identifying these persons.

Exercise therapy and patient education versus intra-articular saline injections in the treatment of knee osteoarthritis: an evidence-based protocol for an open-label randomised controlled trial (the DISCO trial).

BACKGROUND: Knee osteoarthritis (OA) is a highly prevalent musculoskeletal condition causing pain, physical disability, and reduced quality of life. Exercise and patient education are non-pharmacological interventions for knee OA unanimously recommended as first-line treatments based on extensive research evidence. However, none of the numerous randomised controlled trials of exercise and education for knee OA has used adequate sham/placebo comparison groups because the 'active' ingredients are unknown. Designing and executing an adequate and 'blindable placebo' version of an exercise and education intervention is impossible. Therefore, using an open-label study design, this trial compares the efficacy of a widely used 'state-of-art' exercise and education intervention (Good Life with osteoarthritis in Denmark; GLAD) with presumably inert intra-articular saline injections on improvement in knee pain in patients with knee OA. METHODS: In this open-label randomised trial, we will include 200 patients with radiographically verified OA of the knee and randomly allocate them to one of two interventions: (i) 8 weeks of exercise and education (GLAD) or (ii) Intra-articular injections of 5 ml isotonic saline every second week for a total of 4 injections. Outcomes are taken at baseline, after 8 weeks of treatment (week 9; primary endpoint) and after an additional 4 weeks of follow-up (week 12). The primary outcome is change from baseline in the Knee Injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale score. Secondary outcomes include the Physical function in Activities of Daily Living, Symptoms, and Knee-related Quality of Life subscales of the KOOS, the patients' global assessment of disease impact, physical performance tests, and presence of knee joint swelling. DISCUSSION: This current trial compares a presumably active treatment (GLAD) with a presumably inert treatment (IA saline injections). Both study interventions have well-established and anticipated similar effects on knee OA symptoms, but the underlying mechanisms are unknown. The interpretation of the results of this trial will likely be difficult and controversial but will contribute to a better understanding of the bias introduced in the effect estimation of classically unblindable exercise and education interventions for knee OA. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT03843931 . Prospectively registered on 18 February 2019.

Risk of Severe Acute Localized Reactions for Different Intraarticular Hyaluronic Acid Knee Injections in a Real-World Setting.

OBJECTIVE: Case reports of severe acute localized reactions (SALR) following intraarticular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA) have been described. We compared surrogate SALR measures between patients using hylan G-F 20 and specific non-hylan G-F 20 HA products. DESIGN: Knee OA patients were identified from the Optum Clinformatics dataset (January 2006 to June 2016), stratified into hylan G-F 20 and non-hylan G-F 20 HA users, matched by single or multiple injection products. Occurrences of surrogate SALR measures including inflammation/infection, intraarticular corticosteroid (CS) injections, arthrocentesis/aspiration, arthrotomy/incision and drainage, and arthroscopy were evaluated within 3 days post-HA. RESULTS: Based on 694,404 HA injections, inflammation/infection rate was rare within 3 days of HA (up to 0.03%), with no statistical differences between hylan G-F 20 and non-hylan G-F 20 groups (matched by single or multiple injection products). The risk of knee arthrotomy/incision and drainage, arthroscopy, or arthrocentesis for hylan G-F 20 (2 mL) 3 weekly injection patients was lower than Hyalgan/Supartz and Orthovisc patients, but greater than Euflexxa patients. Overall, we found that Hylan G-F 20 (2 mL) 3 weekly injection had lower SALR rates compared to Hyalgan/Supartz and Orthovisc. However, Hylan G-F 20 (2 mL) 3 weekly injection had slightly higher rates of SALR when compared to Euflexxa. Among the single injection products, Hylan G-F 20 (6 mL) single injection had lower rates of SALR than Monovisc and Gel-One. CONCLUSIONS: This study shows no clear correlation between avian-derived or cross-linked products and SALR and provides evidence against avian-derived products or crosslinking as a source for these reactions.

Osteoarthritis Research Society International (OARSI): Past, present and future.

We provide a detailed account of the origin and establishment of the Osteoarthritis Research Society International (OARSI) and celebrate its history from inception to the current day. We discuss the mission, vision and strategic objectives of OARSI and how these have developed and evolved over the last 3 decades. We celebrate the achievements of the society as we approach its 30th birthday, honor the entire presidential line and respectfully pay tribute to the past presidents who are no longer with us. We reflect on the strong foundations of our society, OARSI's efforts to disseminate understanding of the health, disability and economic burdens of osteoarthritis (OA) to policymakers, and the exciting initiatives to make the society inclusive and international. We thank our corporate and industrial sponsors, who have supported us over many years, without whom our annual congresses would not have been possible. We celebrate our longstanding strategic partnership with our publisher, Elsevier, and the successful launch of our new journal Osteoarthritis and Cartilage Open, the most significant new development in our dissemination toolbox. For the first time in the history of the organization, our annual congress was cancelled in April 2020 and the 2021 meeting will be virtual. Despite the numerous challenges posed by the ongoing COVID-19 pandemic and the need to adapt quickly to a rapidly changing landscape, we must remain optimistic about the future. We will take advantage of new exciting opportunities to advance our mission and vision to enhance the quality of life of persons with OA.