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Kevin L Ong,1 Maria Runa,1 Edmund Lau,2 Roy D Altman3 1Biomedical Engineering, Exponent, Inc, Philadelphia, PA, USA; 2Health Sciences, Exponent, Inc, Menlo Park, CA, USA; 3School of Medicine, University of California, Los Angeles, CA, USA Purpose: Although knee arthroplasty (KA) is the largest source of hospitalization costs for knee osteoarthritis (OA), some studies have suggested reducing the use of “low-value” interventions, such as intra-articular hyaluronic acid (HA), to lower health care costs. However, those studies fail to consider that HA has demonstrated benefits in extending time to more costly KA or avoiding KA altogether. We evaluated 1) the overall knee OA costs (direct) within a 2-year period; 2) the relative contribution of HA and KA costs; 3) the direct cost savings from HA patients not undergoing KA.Patients and methods: Knee OA patients were identified from the Optum Clinformatics data set, which includes physician, facility, and pharmacy claims data from privately insured patients of all ages. Patients were stratified in the no HA, non-hylan G-F 20, and hylan G-F 20 cohorts. The cumulative costs (payer perspective) were evaluated for all knee OA-related claims (adjusted to Consumer Price Index Jan 2017$) for patients who had at least 2 years follow-up. Costs were stratified into various clinical categories.Results: The study cohort included 2,030,497 knee OA patients, of which 65,144 patients (3.2%) underwent KA. The cost of treating knee OA within the 2-year follow-up period was estimated to be $4.99 billion (B). The majority of the costs (69%) were attributed to KA patients (3.2% of patients). In all, 15.9% of the HA patients underwent KA within 2 years, but HA only contributed 1.7% to the total costs for these patients. The remaining 84.1% of HA patients did not undergo KA, which saved an estimated total of $1.54B (average $20,740 per patient) or 83.9%, after accounting for their non-KA therapies.Conclusion: Our study estimated substantial cost savings through a large percentage of HA patients not undergoing KA. Although a fraction of patients moved on from their conservative therapy to undergo KA within the 2-year period, HA attributed to

Larry E Miller,1 Roy D Altman,2 Louis F McIntyre3 1Miller Scientific Consulting, Inc., Asheville, NC, 2Department of Rheumatology, University of California Los Angeles, Los Angeles, CA, 3Northwell Physician Partners, Sleepy Hollow, NY, USA Abstract: Hyaluronic acid (HA) is a commonly prescribed treatment for knee pain resulting from osteoarthritis (OA). Although numerous HA products have been approved for use by the US Food and Drug Administration, the efficacy of HA injections for knee OA remains disputed with meta-analyses and societal clinical guidelines drawing disparate conclusions. The American Academy of Orthopaedic Surgeons (AAOS) recently published a best-evidence systematic review and concluded that available data did not support the routine use of HA for knee OA. The purpose of the current article is to highlight issues that confound interpretation of meta-analyses on HA for knee OA, to provide realistic estimates of the true efficacy of HA injections in knee OA, and to provide commentary on the methods and conclusions from the AAOS systematic review. In general, the clinical benefit of HA is underestimated using conventional meta-analytic techniques. When accounting for differential control group effects in HA studies, it can be reasonably concluded that HA injections may be beneficial to an appreciable number of patients with knee OA. In addition, the systematic review methodology used by AAOS was questionable due to exclusion of numerous relevant studies and inclusion of studies that used HAs not approved for use in the US, both of which underestimated the true efficacy of HA injections. Overall, the efficacy of HA injections for knee OA is likely better than previously reported. Future clinical trials and meta-analyses should account for differential control group effects in order to avoid the continued confusion surrounding HA injection efficacy. Keywords: effect size, hyaluronic acid, injection, knee, minimal important difference, osteoarthritis

OBJECTIVES: Nonsteroidal anti-inflammatory drugs have dose-related adverse effects. Topical nonsteroidal anti-inflammatory drugs may offer local efficacy with low systemic drug levels. This study assessed the efficacy and safety of topical diclofenac sodium 1% gel (DSG) in mild to moderate symptomatic knee osteoarthritis. METHODS: In a randomized, double-blind, vehicle-controlled trial, 492 adults aged >or=35 years with symptomatic knee osteoarthritis of >or=6 months' duration were randomized to DSG 4 g (n = 254) or vehicle (n = 238) 4 times daily for 12 weeks. Primary efficacy outcomes at week 12 were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, WOMAC physical function subscale, and global rating of disease. Secondary outcomes included these outcomes assessed after 1, 4, and 8 weeks, and pain on movement assessed using a 100-mm visual analog scale. All adverse events were recorded. RESULTS: At week 12, the DSG group had significant decreases versus the vehicle group in mean WOMAC pain (P = 0.01), mean WOMAC physical function (P = 0.001), and mean global rating of disease (P < 0.001). Efficacy outcomes significantly favored DSG versus vehicle beginning at week 1. Application site reactions occurred in 5.1% and 2.5% of patients in the DSG and vehicle groups, respectively. The incidence of gastrointestinal disorders was 5.9% with DSG and 5.0% with vehicle. CONCLUSIONS: Over a 3-month treatment period, topical treatment with DSG achieved statistically and clinically significant improvements of pain and measures of physical function in patients with knee osteoarthritis.Copyright © 2009 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To report the FLEXX trial, the first well-controlled study assessing the safety and efficacy of Euflexxa (1% sodium hyaluronate; IA-BioHA) therapy for knee osteoarthritis (OA) at 26 weeks. METHODS: This was a randomized, double-blind, multicenter, saline-controlled study. Subjects with chronic knee OA were randomized to 3 weekly intra-articular (IA) injections of either buffered saline (IA-SA) or IA-BioHA (20 mg/2 ml). The primary efficacy outcome was subject recorded difference in least-squares means between IA-BioHA and IA-SA in subjects' change from baseline to week 26 following a 50-foot walk test, measured via 100-mm visual analog scale (VAS). Secondary outcome measures included Osteoarthritis Research Society International responder index, Western Ontario McMaster University Osteoarthritis Index VA 3.1 subscales, patient global assessment, rescue medication, and health-related quality of life (HRQoL) by the SF-36. Safety was assessed by monitoring and reporting vital signs, physical examination of the target knee following injection, adverse events, and concomitant medications. RESULTS: Five hundred eighty-eight subjects were randomized to either IA-BioHA (n = 293) or IA-SA (n = 295), with an 88% 26 week completion rate. No statistical differences were noted between the treatment groups at baseline. In the IA-BioHA group, mean VAS scores decreased by 25.7 mm, compared with 18.5 mm in the IA-SA group. This corresponded to a median reduction of 53% from baseline for IA-BioHA and a 38% reduction for IA-SA. The difference in least-squares means was -6.6 mm (P = 0.002). Secondary outcome measures were consistent with significant improvement in Osteoarthritis Research Society International responder index, HRQoL, and function. Both IA-SA and IA-BioHA injections were well tolerated, with a low incidence of adverse events that were equally distributed between groups. Injection-site reactions were reported by 1 (<1%) subject in the IA-SA group and 2 (1%) in the IA-BioHA group. CONCLUSIONS: IA-BioHA therapy resulted in significant OA knee pain relief at 26 weeks compared with IA-SA. Subjects treated with IA-BioHA also experienced significant improvements in joint function, treatment satisfaction, and HRQoL. Copyright © 2009 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Objective: Meta-analysis of randomized controlled trials (RCTs)--of a hip powder of Rosa canina (rosehip) preparation for symptomatic treatment of osteoarthritis (OA), in order to estimate the empirical efficacy as a pain reducing compound.Method: RCTs from systematic searches were included if they explicitly stated that OA patients were randomized to either rosehip or placebo. The primary outcome was reduction in pain calculated as effect size (ES), defined as the standardized mean difference (SMD). As secondary analysis the number of responders to therapy was analyzed as Odds Ratios (OR), and expressed as the Number Needed to Treat (NNT). Restricted Maximum Likelihood (REML) methods were applied for the meta-analyses using mixed effects models.Results: The three studies (287 patients and a median trial-duration of 3 months)--all supported by the manufacturer (Hyben-Vital International)--showed a reduction in pain scores by rosehip powder (145 patients) compared to placebo (142 patients): ES of 0.37 [95% confidence interval (CI): 0.13-0.60], P=0.002. Test for homogeneity seemed to support that the efficacy was consistent across trials (I(2)=0%). Thus it seems reasonable to assume that the three studies were measuring the same overall effect. It seemed twice as likely that a patient allocated to rosehip powder would respond to therapy, compared to placebo (OR=2.19; P=0.0009); corresponding to a NNT of six (95% CI: 4-13) patients.Conclusions: Although based on a sparse amount of data, the results of the present meta-analysis indicate that rosehip powder does reduce pain; accordingly it may be of interest as a nutraceutical, although its efficacy and safety need evaluation and independent replication in a future large-scale/long-term trial. [ABSTRACT FROM AUTHOR]

Background: The potential benefit of hyaluronans in alleviating pain associated with osteoarthritis (OA) in joints other than the knee is of increasing interest. This double-blind, randomized, controlled study examined the safety and efficacy of intra-articular sodium hyaluronate (Hyalgan ) in the treatment of pain associated with ankle OA. Materials and Methods: Thirty consecutive patients with ankle OA documented by X-ray were randomized to treatment with five weekly injections of either sodium hyaluronate 2 mL (HYL) or phosphate-buffered saline 2 mL (control) in the tibiotalar joint. The primary endpoint was pain on movement and weightbearing using the Ankle Osteoarthritis Scale (AOS) 3 months after injection (a 100-mm visual analog scale [VAS]). Additional measures included the Western Ontario and McMaster Universities (WOMAC) OA Index and patient global assessment through 6 months; the Short Form-12 (SF-12) Health Survey at 3 months and 6 months; and all reported adverse events (AEs). Results: The study groups differed only in age, baseline WOMAC pain, and AOS total scores; 80% of the HYL and 73% of the control patients completed the study. At Month 3, the primary endpoint of the study, the HYL group demonstrated a significantly greater improvement from baseline in AOS total score than did the control group (HYL: -17.4 ± 5.0 mm; Control: -5.1 ± 4.0 mm; p = 0.0407). The incidence of AEs was low, with no significant differences between the groups. There were no post-injection flares. Conclusion: Our study suggests that sodium hyaluronate may be a safe and effective option for pain associated with ankle OA, although larger studies are needed. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the impact of patient age at symptom onset on radiographic joint damage at study entry, and on subsequent progression of damage in a cohort of patients with early seropositive rheumatoid arthritis (RA). METHODS: We studied 186 patients with RA of <15 months' duration. All patients had active disease and had not received disease-modifying antirheumatic drugs. At study entry and during followup, total Sharp scores (TSS), RA-associated joint space narrowing (RA-JSN), and erosions were determined on hand and foot radiographs. Baseline radiographs were also scored for osteoarthritis (OA)-related JSN (OA-JSN) and osteophytes. Older patients (>55 years) and younger patients (

Two major trials recently compared the GI adverse effects of celecoxib and rofecoxib with those of traditional NSAIDs. What did the researchers find, and what are the clinical implications? [ABSTRACT FROM AUTHOR]

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 ​= ​642) perceived their knee pain as a greater threat to them than Cluster 2 ("Unconcerned confident" [hypothesized favorable profile]; n ​= ​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., Competing Interests: All authors have completed the Osteoarthritis and Cartilage Open authors’ disclosure form and declare that they have no competing interests to report., (© 2023 The Author(s).)

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., Competing Interests: Competing interests: This study had no competing financial interests. Interests disclosed in the International Committee of Medical Journal Editors (ICMJE) conflict of interest forms are as follows: LKS has received grants from the Health Research Council of New Zealand, royalties/licenses from UpToDate and consulting fees from Pharmac NZ. AD has received grants for the research project disclosed as funding. IKH has received consulting fees from Novartis and GSK and is a member of the OARSI executive committee. MK has received grants from IMI APPROACH and the Dutch Arthritis Society, royalties/licences from Wolters Kluwer and Springer Verlag, and consulting fees from Abbvie, Pfizer, Kiniksa Flexion, Galapagos, CHDR, Novartis and UCB, and she is a member of the OARSI board, the EULAR council and President of the Dutch Society for Rheumatology., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with acute to subacute multifocal neurologic abnormalities often have a unique presentation, and their diagnosis and management can be challenging. We present the case of a 40-year-old patient who presented with a 4-day history of confusion, bradyphrenia, right facial droop, bilateral lower limb weakness, urinary incontinence, and hypothermia. This case highlights the diagnostic approach to patients with subacute multifocal neurologic abnormalities, the importance of considering coexisting systemic illnesses in the diagnosis, and their management. Readers will explore the diagnostic steps our group has considered to reach our final diagnosis and the importance of management for our leading diagnosis., (© 2023 American Academy of Neurology.)

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/m 2 ), 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., Competing Interests: Declaration of interests The Parker Institute is supported by a core grant from the Oak Foundation (OCAY-18–774-OFIL). AD has received grants to this project from IMK Almene Fond, Erna Hamilton's Foundation (Minister Erna Hamilton's Scholarship for Science and Art), the AP Møller Foundation (AP Møller and wife Chastine McKinney Møller'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. FB has received consulting fees from Horizon Therapeutics. FCM has received grants from Innovation Fund Denmark; and payment or honoraria from Varian and Siemens Healthineers. IKH has received grants from Pfizer and Lily; and payment or honoraria from Novartis and GSK. LT has received payment or honoraria from Eli Lilly, Novartis, and Janssen; and is on the advisory board for Bristol Meyers Squibb and Janssen. MH is on the European Advisory Board for Thuasne Group. MK has received grants from the Innovative Medicines Initiative (APPROACH project) and Dutch Arthritis Society; royalties or licenses from Wolters Kluwer and Springer Verlag; consulting fees for Abbvie, Pfizer, Kiniksa, Flexion, Galapagos, Centre for Human Drug Research, Novartis, and UCB; payment or honoraria from Galapagos and Jansen; and is a member of the Osteoarthritis Research Society International board, a member of the European Alliance of Associations for Rheumatology (EULAR) council and President for the Dutch Society for Rheumatology. PGC has received consulting fees from AbbVie, AstraZeneca, Eli Lilly, Galapagos, GlaxoSmithKline, Grunenthal, Janssen, Levicept, Merck, Novartis, Pfizer, Regeneron, Stryker, and UCB; payment or honoraria from AbbVie; and support from AbbVie to congress attendance. LKS has received grants from the Health Reserach Council of New Zealand amd consulting fees from Pharmac. GMM has received support for attending meeting from Janssen; and is president for the Irish Society of Rheumatology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.

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.

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.

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., Competing Interests: The authors have no conflicts to declare in connection with this article., (© 2021 The Author(s).)

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.

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.

Background: Joint replacements continue to occur during a rheumatoid arthritis (RA) patient's lifetime despite significant advances in available treatment options. The purpose of this study was to examine and quantify synovitis in surgically operated joints by ultrasound (US) in RA patients starting a new therapeutic agent., Methods: RA subjects were enrolled in either tocilizumab or tofacitinib open-label, investigator-initiated trials and were assessed by ultrasound. In a subset of RA patients with joint replacements and/or operations of joint areas (OJA; e.g. joint arthroscopies, fusions, and synovectomies), joint-level scores of synovitis were compared between replaced joints, OJAs, and native joints. Joint-level synovitis was measured by grayscale (GSUS (0-3)) and power Doppler (PDUS (0-3)) at baseline and follow-up (3-6 months). McNemar's test or Wilcoxon signed rank test utilized the mixed effects ordinal logistic regression models., Results: Twenty RA patients had a total of 25 replaced joints and 24 OJA. All replaced joints had GSUS> 1 and 92% had PDUS> 1 at baseline, while OJA and native joints had lower evidence of GSUS> 1 (37.5, 38% respectively) and PDUS> 1 (45.8, 62% respectively). GSUS and PDUS semiquantitative scores improved significantly with treatment in replaced joints ( p  = 0.01, p  = 0.007), and native joints ( p  < 0.001 both), but not OJA., Conclusions: In RA, joint replacement does not eliminate or prevent ultrasound measured synovitis, where all replaced joints have some evidence of US synovitis. US can also act as a potential marker of response to therapy in replaced joints. Scoring US synovitis in replaced joints should be considered in ultrasound RA clinical trials., Trial Registration: ClinicalTrials.gov NCT01717859 (registered 10/31/2012); ClinicalTrials.gov NCT02321930 (registered 12/22/2014)., Competing Interests: Competing interestsEAC: none reported; GSK: none reported; JB: none reported; RDA serves as a consultant for Ferring, Flexion, GSK, Novartis, Olatec, and Pfizer; JF: none reported; ARFS: none reported; DAE: none reported; VKR has received research support and grants from Genentech (IST grant), Pfizer (IST grant), Mallinkrodt (IST grant), BMS (ad board), and Amgen (DSMB)., (© The Author(s) 2020.)

Objective: To develop an evidence-based guideline for the comprehensive management of osteoarthritis (OA) as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA., Methods: We identified clinically relevant population, intervention, comparator, outcomes questions and critical outcomes in OA. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available educational, behavioral, psychosocial, physical, mind-body, and pharmacologic therapies for OA. Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. A Voting Panel, including rheumatologists, an internist, physical and occupational therapists, and patients, achieved consensus on the recommendations., Results: Based on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. Strong recommendations were made for exercise, weight loss in patients with knee and/or hip OA who are overweight or obese, self-efficacy and self-management programs, tai chi, cane use, hand orthoses for first carpometacarpal (CMC) joint OA, tibiofemoral bracing for tibiofemoral knee OA, topical nonsteroidal antiinflammatory drugs (NSAIDs) for knee OA, oral NSAIDs, and intraarticular glucocorticoid injections for knee OA. Conditional recommendations were made for balance exercises, yoga, cognitive behavioral therapy, kinesiotaping for first CMC OA, orthoses for hand joints other than the first CMC joint, patellofemoral bracing for patellofemoral knee OA, acupuncture, thermal modalities, radiofrequency ablation for knee OA, topical NSAIDs, intraarticular steroid injections and chondroitin sulfate for hand OA, topical capsaicin for knee OA, acetaminophen, duloxetine, and tramadol., Conclusion: This guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies., (© 2020, American College of Rheumatology.)

Background: Intra-articular hyaluronic acid (HA) injections and oral nonsteroidal anti-inflammatory drugs (NSAIDs) are common treatments for symptomatic knee osteoarthritis (OA). However, the comparative effects of these treatments are unclear., Purpose: To compare the efficacy and safety of intra-articular HA injections compared with oral NSAIDs for the treatment of knee OA., Study Design: Systematic review; Level of evidence, 1., Methods: We systematically searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for randomized trials of knee OA treatment with HA injections compared with oral NSAIDs. The main outcomes were knee pain, knee function, adverse events (AEs), serious AEs, study withdrawals, and study withdrawals because of AEs. Pooled effect sizes were reported at the final follow-up with standardized mean difference (SMD) for efficacy outcomes and risk ratio (RR) for safety outcomes., Results: In 6 randomized trials of 831 patients (414 HA, 417 NSAIDs), with follow-up ranging from 5 to 26 weeks, HA injections were associated with small, statistically significant improvements in knee pain (SMD, 0.15; P = .04) and knee function (SMD, 0.23; P = .01) compared with oral NSAIDs. The risk of AEs was lower with HA compared with NSAIDs (19.8% vs 29.0%; RR, 0.74; P = .01). The risk of a serious AE (RR, 1.37; P = .71), study withdrawal (RR, 1.05; P = .68), or study withdrawal because of an AE (RR, 0.65; P = .22) was comparable between groups. Gastrointestinal concerns were the most frequent AE reported, occurring more often with NSAIDs (23.4% vs 14.1%; P = .001). AEs reported more frequently with HA injections were injection site pain (11.7% vs 4.7%; P < .001), headache (8.4% vs 4.4%; P = .03), and arthralgia (8.1% vs 2.9%; P = .001). Significant heterogeneity or publication bias was not observed for any outcome., Conclusion: Comparing short-term outcomes of HA injections with oral NSAIDs for treatment of knee OA, HA injections provided statistically significant but not clinically important improvements in knee pain and function, along with a lower overall risk of AEs., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: L.E.M. has consulting affiliations with DePuy Synthes and OsteoArthritis Centers of America. M.F. has received honoraria from Fidia Pharma and hospitality payments from DePuy and Ipsen Innovation. R.D.A. has received speaking fees from Genzyme and Iroko Pharmaceuticals; hospitality payments from Bioventus; honoraria from Teva Pharmaceuticals; and consulting fees from Meda Pharmaceuticals, Insys Therapeutics, Ferring Pharmaceuticals, Pfizer, Genzyme, Iroko Pharmaceuticals, Novartis, Merck Sharp & Dohme, and Sanofi-Aventis. He also reports affiliations with GlaxoSmithKline, Sorrento, and Theralogix. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

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.

Activation of the NLRP3 inflammasome induces maturation of IL-1β and IL-18, both validated targets for treating acute and chronic inflammatory diseases. Here, we demonstrate that OLT1177, an orally active β-sulfonyl nitrile molecule, inhibits activation of the NLRP3 inflammasome. In vitro, nanomolar concentrations of OLT1177 reduced IL-1β 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-1β 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-1β 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-1β 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-1β 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-1β 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., Competing Interests: Conflict of interest statement: C.A.D. serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, and receives compensation. L.A.B.J. serves on Olatec’s Scientific Advisory Board and receives compensation. J.P.S.L. has equity in Olatec. D.B.S. serves as Chairman and Chief Executive Officer of Olatec, R.B.B. serves as Chief Operating Officer of Olatec, and C.L.S. and R.D.A. serve on Olatec’s Scientific Advisory Board., (Copyright © 2018 the Author(s). Published by PNAS.)

Objective Summarize the biologic effects of Supartz FX for knee osteoarthritis (OA), the first worldwide clinically approved intra-articular (IA) hyaluronic acid (HA) product. Design To determine the mechanism of action from preclinical and clinical studies, a literature search was conducted of Supartz FX using academic databases from 1987 to 2016. Articles on Supartz FX that deal with its mechanisms of action were extracted, categorized, and reviewed. Results Supartz FX has 2 potential mechanisms of action: (1) biomechanical: IA Supartz FX directly improves the viscoelasticity and lubrication of synovial fluid; (2) physiologic: IA Supartz FX penetrates synovium and cartilage tissues to reach HA receptors on the surface of synoviocytes and chondrocytes. In synovium, suppression of gene expression in inflammatory mediators results in improved endogenous HA production, improved properties of synovial fluid, and reduction in pain. In cartilage, suppression of gene expression of collagenases and aggrecanases suppresses cartilage degeneration. Conclusion The net results of basic and clinical studies is that IA Supartz FX provides a more favorable biomechanical and functional environment in the knee joint. Hence, it is not only a lubricant but is also physiologically active. These actions may help explain both short- and long-term improvement in pain and function often achieved from IA Supartz FX in knee OA.

Objectives: Hyaluronic acid and corticosteroids are common intra-articular (IA) therapies widely used for the management of mild to moderate knee osteoarthritis (OA). Many trials evaluating the efficacy of IA administered therapies commonly use IA saline injections as a placebo comparator arm. Using a systematic review and meta-analysis, our objective was to assess the clinical benefit associated with use of IA saline in trials of IA therapies in the treatment of patients with painful knee OA., Methods: MEDLINE and Embase databases were searched for articles published up to and including August 14th, 2014. Two reviewers assessed the eligibility of potential reports and the risk of bias of included trials. We analyzed short (≤3 months) and long-term (6-12 months) pain reduction of the saline arm of included trials using standardized mean differences (SMDs; estimated assuming a null effect in a comparator group) that were combined and weighted using a random effects model. Treatment-related adverse events (AEs) were tabulated and presented using descriptive statistics., Results: From 40 randomized controlled trials (RCTs) eligible for inclusion only 38 provided sufficient data to be included in the meta-analysis. Based on data with moderate inconsistency IA saline was found to significantly improve short-term knee pain in 32 studies involving 1705 patients (SMD = -0.68; 95% CI: -0.78 to -0.57; P < 0.001; I(2) = 50%). Long-term knee pain was significantly decreased following IA injection with saline in 19 studies involving 1445 patients (SMD = -0.61; 95% CI: -0.76 to -0.45; P < 0.001) with a substantial degree of inconsistency (I(2) = 74%). Overall, 29 of the included trials reported on adverse events, none of which found any serious treatment-related AEs following IA injection with saline., Conclusions: Pain relief observed with IA saline should prompt health care providers to consider the additional effectiveness of current IA treatments that use saline comparators in clinical studies, and challenges of identifying IA saline injection as a "placebo.", (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Knee osteoarthritis (OA) is a common and often disabling joint disorder among adults that may result in impaired activity and daily function. A variety of treatment options are currently available and prescribed for knee OA depending on the severity of the disorder and physician preference. Intra-articular hyaluronic acid (IA-HA) injection is a treatment for knee OA that reportedly provides numerous biochemical and biological benefits, including shock absorption, chondroprotection, and anti-inflammatory effects within the knee. Clarity is needed as to whether the available IA-HA products should be considered for therapy as a group or whether there are significant differences in the products that need to be considered in treatment of OA of the knee., Purpose: To determine whether there are differences in efficacy and safety with respect to intrinsic properties of available IA-HA injections for knee OA., Study Design: Meta-analysis., Methods: A comprehensive literature search of the Medline, EMBASE, and PubMed databases was conducted for all existing randomized trials of IA-HA. The primary outcome measure analyzed was the mean pain score at the reported follow-up nearest to 26 weeks after injection. Pooled efficacy and safety results were recorded for subgroupings of HA product characteristics., Results: A total of 68 studies were included for analysis. Products with an average molecular weight ≥3000 kDa provided favorable efficacy results when compared with products of an average molecular weight <3000 kDa. Products with a molecular weight ≥3000 kDa demonstrated significantly fewer discontinuations due to treatment-related adverse events than did ≤1500 kDa counterparts, while trial discontinuation rates were similar between biological fermentation-derived HA products and avian-derived HA. The results did not demonstrate a significant difference in the occurrence of effusion across molecular weight subgroups. Additionally, biological fermentation-derived HA had a significantly smaller incidence of effusion than did avian-derived HA. Biological fermentation-derived HA demonstrated fewer acute flare-ups at the injection site than did avian-derived HA products, while high-molecular-weight products demonstrated the highest rate of injection site flare-up., Conclusion: Despite similarities, IA-HA products should not be treated as a group, as there are differences in IA-HA products that influence both efficacy and safety. In the available literature, IA-HA products with a molecular weight ≥3000 kDa and those derived from biological fermentation relate to superior efficacy and safety-factors that may influence selection an IA-HA product for OA of the knee., (© 2015 The Author(s).)

Objective: The aim was to identify factors explaining inconsistent observations concerning the efficacy of intra-articular hyaluronic acid compared to intra-articular sham/control, or non-intervention control, in patients with symptomatic osteoarthritis, based on randomized clinical trials (RCTs)., Methods: A systematic review and meta-regression analyses of available randomized trials were conducted. The outcome, pain, was assessed according to a pre-specified hierarchy of potentially available outcomes. Hedges׳s standardized mean difference [SMD (95% CI)] served as effect size. REstricted Maximum Likelihood (REML) mixed-effects models were used to combine study results, and heterogeneity was calculated and interpreted as Tau-squared and I-squared, respectively., Results: Overall, 99 studies (14,804 patients) met the inclusion criteria: Of these, only 71 studies (72%), including 85 comparisons (11,216 patients), had adequate data available for inclusion in the primary meta-analysis. Overall, compared with placebo, intra-articular hyaluronic acid reduced pain with an effect size of -0.39 [-0.47 to -0.31; P < 0.001], combining very heterogeneous trial findings (I(2) = 73%). The three most important covariates in reducing heterogeneity were overall risk of bias, blinding of personnel and trial size, reducing heterogeneity with 26%, 26%, and 25%, respectively (Interaction: P ≤ 0.001). Adjusting for publication/selective outcome reporting bias (by imputing "null effects") in 24 of the comparisons with no data available reduced the combined estimate to -0.30 [-0.36 to -0.23; P < 0.001] still in favor of hyaluronic acid., Conclusion: Based on available trial data, intra-articular hyaluronic acid showed a better effect than intra-articular saline on pain reduction in osteoarthritis. Publication bias and the risk of selective outcome reporting suggest only small clinical effect compared to saline., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Intra-articular hyaluronic acid (IA-HA) injections are a treatment for knee osteoarthritis (OA), although current literature provides mixed results with regard to their efficacy. We will review a randomized controlled trial (RCT) and subsequent extension trial in order to identify factors that are associated with outcomes in patients with knee OA who received IA-HA., Methods: We used data recorded by the FLEXX trial and extension trial for secondary analysis of potential prognostic factors. Linear regression was used to examine the predictors of outcomes at 6- and 12-month follow-up visits., Results: Sixty percent of all patients presented with a Kellgren Lawrence (K-L) grade 3. Patients with high baseline outcome scores and a K-L grade 3 demonstrated less response than individuals within an earlier stage of knee OA, although results for both K-L grade 2 and K-L grade 3 patients still showed benefit. Those with more severe radiographic change K-L grade 3 often had a better response with the second series of IA-HA injections. Significantly greater positive response in all outcomes was demonstrated for the patient subgroup classified as K-L grade 2, when compared with K-L grade 3 patients., Conclusions: The results demonstrate that IA-HA for knee OA was of greater benefit in those with less severe radiographic changes. However, those with more severe radiographic change often had a better response with the second course of IA-HA. Similar analyses are required in order to determine if these results are unique to Euflexxa, or if these results are consistent with other available IA-HA agents.

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published a treatment algorithm for the management of knee osteoarthritis (OA) in 2014, which provides practical guidance for the prioritization of interventions. Further analysis of real-world data for OA provides additional evidence in support of pharmacological interventions, in terms of management of OA pain and function, avoidance of adverse events, disease-modifying effects and long-term outcomes, e.g., delay of total joint replacement surgery, and pharmacoeconomic factors such as reduction in healthcare resource utilization. This article provides an updated assessment of the literature for selected interventions in OA, focusing on real-life data, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA in primary care clinical practice, in support of the clinicians' individualized assessment of the patient. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) is recommended, for which high-quality evidence is provided only for the prescription formulations of patented crystalline glucosamine sulfate and chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs without the systemic safety concerns. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk:benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends chronic symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) including glucosamine sulfate (GS) and chondroitin sulfate (CS) as first-line therapy for knee osteoarthritis (OA). Numerous studies are published on the use of SYSADOAs in OA; however, the efficacy of this class is still called into question largely due to the regulatory status, labeling and availability of these medications which differ substantially across the world. Examination of the evidence for the prescription patented crystalline GS (pCGS) formulation at a dose of 1500mg once-daily demonstrates superiority over other GS and glucosamine hydrochloride (GH) formulations and dosage regimens. Thus, the ESCEO task force advocates differentiation of prescription pCGS over other glucosamine preparations. Long-term clinical trials and real-life studies show that pCGS may delay joint structural changes, suggesting potential benefit beyond symptom control when used early in the management of knee OA. Real-life pharmacoeconomic studies demonstrate a long-term reduction in the need for additional pain analgesia and non-steroidal anti-inflammatory drugs (NSAIDs) with pCGS, with a significant reduction of over 50% in costs associated with medications, healthcare consultations and examinations over 12 months. Furthermore, treatment with pCGS for at least 12 months leads to a reduction in the need for total joint replacement for at least 5 years following treatment cessation. Thus, pCGS (1500mg od) is a logical choice to maximize clinical benefit in OA patients, with demonstrated medium-term control of pain and lasting impact on disease progression., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Clinical practice guidelines are of increasing importance in the decision making for the treatment of knee osteoarthritis. Inconsistent recommendations regarding the use of intra-articular hyaluronic acid for the treatment of knee osteoarthritis have led to confusion among treating physicians., Methods: Literature search to identify clinical practice guidelines that provide recommendations regarding the use of intra-articular hyaluronic acid treatment for knee osteoarthritis was conducted. Included guidelines were appraised using the AGREE II instrument. Guideline development methodologies, how the results were assessed, the recommendation formation, and work group composition were summarized., Results: Overall, 10 clinical practice guidelines were identified that met our inclusion criteria. AGREE II domain scores were variable across the included guidelines. The methodology utilized across the guidelines was heterogeneous regarding the evidence inclusion criteria, analysis of evidence results, formulation of clinical practice recommendations, and work group composition. The recommendations provided by the guidelines for intra-articular hyaluronic acid treatment for knee osteoarthritis are highly inconsistent as a result of the variability in guideline methodology. Overall, 30% of the included guidelines recommended against the use of intra-articular hyaluronic acid in the treatment of knee osteoarthritis, while 30% deemed the treatment an appropriate intervention under certain scenarios. The remaining 40% of the guidelines provided either an uncertain recommendation or no recommendation at all, based on the high variability in reviewed evidence regarding efficacy and trial quality., Conclusion: There is a need for a standard "appropriate methodology" that is agreed upon for osteoarthritis clinical practice guidelines in order to prevent the development of conflicting recommendations for intra-articular hyaluronic acid treatment for knee osteoarthritis, and to assure that treating physicians who are utilizing these guidelines are making their clinical decisions on the best available evidence. At present, the inconsistent recommendations provided for intra-articular hyaluronic acid treatment make it difficult for clinical professionals to determine its appropriateness when treating patients with knee osteoarthritis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Introduction: Diclofenac is used for the treatment of osteoarthritis (OA); however, like other nonsteroidal anti-inflammatory drugs (NSAIDs) it can be associated with serious dose-related adverse events (AEs). Low-dose SoluMatrix® diclofenac has been developed to provide efficacy at lower diclofenac doses. A recently published Phase III study evaluated the efficacy and safety of SoluMatrix diclofenac 35 mg twice daily (b.i.d.) and thrice daily (t.i.d.) in patients with OA pain treated for 12 weeks., Methods: This Phase III multicenter, open-label study assessed the safety of SoluMatrix diclofenac in patients with OA dosed up to 52 weeks (ClinicalTrials.gov: NCT01510912). The study enrolled 602 chronic NSAID/acetaminophen users, aged ≥40 years with OA of the knee or hip. Patients received SoluMatrix diclofenac 35 mg b.i.d., which could be increased to t.i.d. and subsequently reduced to b.i.d. as needed. Safety assessments included AEs, vital signs, physical examination findings, 12-lead electrocardiogram, and clinical laboratory test results. Patient-reported outcomes were evaluated by the Short Form-36 (SF-36)., Results: A total of 601 patients received SoluMatrix diclofenac; 373 of 601 patients (62.1%) received treatment for ≥11 months. The most frequent AEs included upper respiratory tract infection, headache, urinary tract infection, diarrhea, nasopharyngitis, and nausea. Serious gastrointestinal, cardiovascular, renal, and hepatic AEs were uncommon. A small proportion (99 patients, 16.5%) of patients discontinued participation in the study due to AEs. Clinically meaningful improvements from baseline in Physical Component Summary Scores of the SF-36 were noted at week 12 and were sustained through week 52. Improvements in six of the eight individual physical and mental SF-36 domains were also noted., Conclusion: SoluMatrix diclofenac treatment for up to 1 year was generally well tolerated in patients with OA pain and associated with improvement in quality of life measures., Trial Registration: www.clinicaltrials.gov identifier: NCT01510912.