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    Metabolic Syndrome, Its Components, and Knee Osteoarthritis: The Framingham Osteoarthritis Study. Niu Jingbo,Clancy Margaret,Aliabadi Piran,Vasan Ramachandran,Felson David T Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:Previous studies have suggested that metabolic syndrome is associated with osteoarthritis (OA). However, analyses have often not included adjustment for body mass index (BMI) and have not addressed whether levels of individual metabolic syndrome components are related to OA. This study was undertaken to examine the relationship of metabolic syndrome and its components with radiographic and symptomatic knee OA. METHODS:Framingham Study subjects were assessed for OA in 1992-1995 and again in 2002-2005. Near the baseline visit, subjects had components of metabolic syndrome assessed. We defined incident radiographic OA as present when a knee without radiographic OA at baseline had a Kellgren/Lawrence grade of ≥2 at follow-up, and defined incident symptomatic OA as present when a knee developed the new combination of radiographic OA and knee pain. After excluding knees with prevalent OA at baseline, we tested the relationship of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria and its components with the risk of incident radiographic OA and symptomatic OA before and after adjusting for BMI using the risk ratio from a binary regression with generalized estimating equations. RESULTS:A total of 991 subjects (55.1% women) with a mean age of 54.2 years were studied, and 26.7% of men and 22.9% of women had metabolic syndrome. Metabolic syndrome and many of its components were associated with both incident radiographic OA and symptomatic OA, but after adjustment for BMI, almost all of these associations became weak and nonsignificant. An association of high blood pressure, especially diastolic pressure, with OA outcomes persisted in both men and women. CONCLUSION:After adjustment for BMI, neither metabolic syndrome nor its components were associated with incident OA. There may be an association between OA and high blood pressure that needs further study. 10.1002/art.40087
    Semiquantitative Imaging Biomarkers of Knee Osteoarthritis Progression: Data From the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium. Collins Jamie E,Losina Elena,Nevitt Michael C,Roemer Frank W,Guermazi Ali,Lynch John A,Katz Jeffrey N,Kent Kwoh C,Kraus Virginia B,Hunter David J Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:To determine the association between changes in semiquantitative magnetic resonance imaging (MRI) biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild-to-moderate osteoarthritis (OA). METHODS:We undertook a nested case-control study as part of the Foundation for the National Institutes of Health Biomarkers Consortium Project. We used multivariable logistic regression models to examine the association between change over 24 months in semiquantitative MRI markers and radiographic and pain progression in knee OA. MRIs were read according to the MRI OA Knee Score system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and effusion-synovitis. RESULTS:The most parsimonious model included changes in cartilage thickness and surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology (C statistic 0.740). Compared with no worsening, worsening in cartilage thickness in ≥3 subregions was associated with 2.8-fold (95% confidence interval [95% CI] 1.3-5.9) greater odds of being a case, and worsening in cartilage surface area in ≥3 subregions was associated with 2.4-fold (95% CI 1.3-4.4) greater odds of being a case. Worsening of meniscal morphology in any region was associated with 2.2-fold (95% CI 1.3-3.8) greater odds of being a case. Worsening effusion-synovitis and Hoffa-synovitis were also associated with a greater odds of being a case (odds ratios 2.7 and 2.0, respectively). CONCLUSION:Twenty-four-month changes in cartilage thickness, cartilage surface area, effusion-synovitis, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that these factors may serve as efficacy biomarkers in clinical trials of disease-modifying interventions for knee OA. 10.1002/art.39731
    Is it Appropriate to Conclude That Muscle Power Is an "Independent" Determinant of Pain and Quality of Life in Knee Osteoarthritis? Comment on the Article by Reid et al. Gao Shu-guang,Zeng Chao,Wei Jie,Lei Guang-hua Arthritis & rheumatology (Hoboken, N.J.) 10.1002/art.39532
    Thigh Muscle Strength Predicts Knee Replacement Risk Independent of Radiographic Disease and Pain in Women: Data From the Osteoarthritis Initiative. Culvenor Adam G,Wirth Wolfgang,Ruhdorfer Anja,Eckstein Felix Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:To determine whether thigh muscle strength predicts the risk of undergoing knee replacement surgery, independent of radiographic severity of osteoarthritis and pain. METHODS:Participants in the Osteoarthritis Initiative study who had received a knee replacement between the 12-month and 60-month follow-up visits (cases) were each matched with 1 control subject (who did not receive a knee replacement over 60 months) for age, sex, height, body mass index, baseline radiographic stage, and location of joint space narrowing. Isometric knee extensor and flexor strength was recorded biennially. The strength examination prior to knee replacement (≤2 years) was termed time 0, that 2 years prior to time 0 was termed time -2, and that 4 years prior to time 0 was termed time -4. Muscle strength in patients and controls was compared using paired t-tests and conditional logistic regression analysis adjusted for pain. RESULTS:One hundred thirty-six participants (60% women, mean ± SD age 65 ± 9 years, body mass index 29 ± 4 kg/m(2) ) received a knee replacement during follow-up, had strength data for at least time 0, and had a matched control. Knee extensor strength at time 0 (primary outcome measure) was significantly lower in female patients compared with controls (P < 0.001, pain-adjusted odds ratio [ORadj ] 1.72, 95% confidence interval 1.16-2.56), but no significant difference was observed in men. Results were similar for knee flexor strength at time 0 and for longitudinal change in extensor and flexor strength between time -2 and time 0. Thigh muscle strength at time -2 or time -4, or change between time -4 and time -2, did not predict the risk of undergoing knee replacement surgery in men or women. CONCLUSION:Thigh muscle strength predicted the risk of undergoing knee replacement surgery in women, but not in men. The results of this study may identify a window during which the risk of undergoing knee replacement surgery in women can be modified. 10.1002/art.39540
    Cartilage regeneration and ageing: Targeting cellular plasticity in osteoarthritis. Varela-Eirin Marta,Loureiro Jesus,Fonseca Eduardo,Corrochano Silvia,Caeiro Jose R,Collado Manuel,Mayan Maria D Ageing research reviews Ageing processes play a major contributing role for the development of Osteoarthritis (OA). This prototypic degenerative condition of ageing is the most common form of arthritis and is accompanied by a general decline, chronic pain and mobility deficits. The disease is primarily characterized by articular cartilage degradation, followed by subchondral bone thickening, osteophyte formation, synovial inflammation and joint degeneration. In the early stages, osteoarthritic chondrocytes undergo phenotypic changes that increase cell proliferation and cluster formation and enhance the production of matrix-remodelling enzymes. In fact, chondrocytes exhibit differentiation plasticity and undergo phenotypic changes during the healing process. Current studies are focusing on unravelling whether OA is a consequence of an abnormal wound healing response. Recent investigations suggest that alterations in different proteins, such as TGF-ß/BMPs, NF-Kß, Wnt, and Cx43, or SASP factors involved in signalling pathways in wound healing response, could be directly implicated in the initiation of OA. Several findings suggest that osteoarthritic chondrocytes remain in an immature state expressing stemness-associated cell surface markers. In fact, the efficacy of new disease-modifying OA drugs that promote chondrogenic differentiation in animal models indicates that this may be a drug-sensible state. In this review, we highlight the current knowledge regarding cellular plasticity in chondrocytes and OA. A better comprehension of the mechanisms involved in these processes may enable us to understand the molecular pathways that promote abnormal repair and cartilage degradation in OA. This understanding would be advantageous in identifying novel targets and designing therapies to promote effective cartilage repair and successful joint ageing by preventing functional limitations and disability. 10.1016/j.arr.2017.12.006
    Predictive Validity of Radiographic Trabecular Bone Texture in Knee Osteoarthritis: The Osteoarthritis Research Society International/Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium. Kraus Virginia Byers,Collins Jamie E,Charles H Cecil,Pieper Carl F,Whitley Lawrence,Losina Elena,Nevitt Michael,Hoffmann Steve,Roemer Frank,Guermazi Ali,Hunter David J, Arthritis & rheumatology (Hoboken, N.J.) OBJECTIVE:To evaluate radiographic subchondral trabecular bone texture (TBT) as a predictor of clinically relevant osteoarthritis (OA) progression (combination of symptom and structural worsening). METHODS:The Foundation for the National Institutes of Health (FNIH) OA Biomarkers Consortium undertook a study of progressive knee OA cases (n = 194 knees with both radiographic and pain progression over 24-48 months) and comparators (n = 406 OA knees not meeting the case definition). TBT parameters were extracted from a medial subchondral tibial region of interest by fractal signature analysis of radiographs using validated semiautomated software. Baseline TBT and time-integrated values over 12 and 24 months were evaluated for association with case status and separately with radiographic and pain progression status, adjusted for age, sex, body mass index, race, baseline Kellgren/Lawrence grade, baseline joint space width, Western Ontario and McMaster Universities Osteoarthritis Index pain score, and pain medication use. C statistics were generated from receiver operating characteristic curves. RESULTS:Relative to comparators, cases were characterized by thinner vertical and thicker horizontal trabeculae. The summed composite of 3 TBT parameters at baseline and over 12 and 24 months best predicted case status (odds ratios 1.24-1.43). The C statistic for predicting case status using the TBT composite score (0.633-0.649) was improved modestly but statistically significantly over the use of covariates alone (0.608). One TBT parameter, reflecting thickened horizontal trabeculae in cases, at baseline and over 12 and 24 months, predicted risk of any progression (radiographic and/or pain progression). CONCLUSION:Although associations are modest, TBT could be an attractive means of enriching OA trials for progressors since it can be generated from screening knee radiographs already standard in knee OA clinical trials. 10.1002/art.40348
    Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture. ,Bhandari Mohit,Einhorn Thomas A,Guyatt Gordon,Schemitsch Emil H,Zura Robert D,Sprague Sheila,Frihagen Frede,Guerra-Farfán Ernesto,Kleinlugtenbelt Ydo V,Poolman Rudolf W,Rangan Amar,Bzovsky Sofia,Heels-Ansdell Diane,Thabane Lehana,Walter Stephen D,Devereaux P J The New England journal of medicine BACKGROUND:Globally, hip fractures are among the top 10 causes of disability in adults. For displaced femoral neck fractures, there remains uncertainty regarding the effect of a total hip arthroplasty as compared with hemiarthroplasty. METHODS:We randomly assigned 1495 patients who were 50 years of age or older and had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. All enrolled patients had been able to ambulate without the assistance of another person before the fracture occurred. The trial was conducted in 80 centers in 10 countries. The primary end point was a secondary hip procedure within 24 months of follow-up. Secondary end points included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health end points. RESULTS:The primary end point occurred in 57 of 718 patients (7.9%) who were randomly assigned to total hip arthroplasty and 60 of 723 patients (8.3%) who were randomly assigned to hemiarthroplasty (hazard ratio, 0.95; 95% confidence interval [CI], 0.64 to 1.40; P = 0.79). Hip instability or dislocation occurred in 34 patients (4.7%) assigned to total hip arthroplasty and 17 patients (2.4%) assigned to hemiarthroplasty (hazard ratio, 2.00; 99% CI, 0.97 to 4.09). Function, as measured with the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score, modestly favored total hip arthroplasty over hemiarthroplasty. Mortality was similar in the two treatment groups (14.3% among the patients assigned to total hip arthroplasty and 13.1% among those assigned to hemiarthroplasty, P = 0.48). Serious adverse events occurred in 300 patients (41.8%) assigned to total hip arthroplasty and in 265 patients (36.7%) assigned to hemiarthroplasty. CONCLUSIONS:Among independently ambulating patients with displaced femoral neck fractures, the incidence of secondary procedures did not differ significantly between patients who were randomly assigned to undergo total hip arthroplasty and those who were assigned to undergo hemiarthroplasty, and total hip arthroplasty provided a clinically unimportant improvement over hemiarthroplasty in function and quality of life over 24 months. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00556842.). 10.1056/NEJMoa1906190
    Hip replacement. Ferguson Rory J,Palmer Antony Jr,Taylor Adrian,Porter Martyn L,Malchau Henrik,Glyn-Jones Sion Lancet (London, England) Total hip replacement is a frequently done and highly successful surgical intervention. The procedure is undertaken to relieve pain and improve function in individuals with advanced arthritis of the hip joint. Symptomatic osteoarthritis is the most common indication for surgery. In paper 1 of this Series, we focus on how patient factors should inform the surgical decision-making process. Substantial demands are placed upon modern implants, because patients expect to remain active for longer. We discuss the advances made in implant performance and the developments in perioperative practice that have reduced complications. Assessment of surgery outcomes should include patient-reported outcome measures and implant survival rates that are based on data from joint replacement registries. The high-profile failure of some widely used metal-on-metal prostheses has shown the shortcomings of the existing regulatory framework. We consider how proposed changes to the regulatory framework could influence safety. 10.1016/S0140-6736(18)31777-X
    Knee replacement. Price Andrew J,Alvand Abtin,Troelsen Anders,Katz Jeffrey N,Hooper Gary,Gray Alastair,Carr Andrew,Beard David Lancet (London, England) Knee replacement surgery is one of the most commonly done and cost-effective musculoskeletal surgical procedures. The numbers of cases done continue to grow worldwide, with substantial variation in utilisation rates across regions and countries. The main indication for surgery remains painful knee osteoarthritis with reduced function and quality of life. The threshold for intervention is not well defined, and is influenced by many factors including patient and surgeon preference. Most patients have a very good clinical outcome after knee replacement, but multiple studies have reported that 20% or more of patients do not. So despite excellent long-term survivorship, more work is required to enhance this procedure and development is rightly focused on increasing the proportion of patients who have successful pain relief after surgery. Changing implant design has historically been a target for improving outcome, but there is greater recognition that improvements can be achieved by better implantation methods, avoiding complications, and improving perioperative care for patients, such as enhanced recovery programmes. New technologies are likely to advance future knee replacement care further, but their introduction must be regulated and monitored with greater rigour to ensure patient safety. 10.1016/S0140-6736(18)32344-4
    Arthroscopic partial meniscectomy versus placebo surgery for a degenerative meniscus tear: a 2-year follow-up of the randomised controlled trial. Sihvonen Raine,Paavola Mika,Malmivaara Antti,Itälä Ari,Joukainen Antti,Nurmi Heikki,Kalske Juha,Ikonen Anna,Järvelä Timo,Järvinen Tero A H,Kanto Kari,Karhunen Janne,Knifsund Jani,Kröger Heikki,Kääriäinen Tommi,Lehtinen Janne,Nyrhinen Jukka,Paloneva Juha,Päiväniemi Outi,Raivio Marko,Sahlman Janne,Sarvilinna Roope,Tukiainen Sikri,Välimäki Ville-Valtteri,Äärimaa Ville,Toivonen Pirjo,Järvinen Teppo L N, Annals of the rheumatic diseases OBJECTIVE:To assess if arthroscopic partial meniscectomy (APM) is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus. METHODS:In this multicentre, randomised, participant-blinded and outcome assessor-blinded, placebo-surgery controlled trial, 146 adults, aged 35-65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis were randomised to APM or placebo surgery. The primary outcome was the between-group difference in the change from baseline in the Western Ontario Meniscal Evaluation Tool (WOMET) and Lysholm knee scores and knee pain after exercise at 24 months after surgery. Secondary outcomes included the frequency of unblinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events and the presence of meniscal symptoms in clinical examination. Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out. RESULTS:In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, -4.3; 95% CI, -11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (-3.2; -8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (-0.4; -1.3 to 0.5). There were no statistically significant differences between the two groups in any of the secondary outcomes or within the analysed subgroups. CONCLUSIONS:In this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery. No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM. 10.1136/annrheumdis-2017-211172
    Association between rainfall and diagnoses of joint or back pain: retrospective claims analysis. Jena Anupam B,Olenski Andrew R,Molitor David,Miller Nolan BMJ (Clinical research ed.) OBJECTIVE:To study the relation between rainfall and outpatient visits for joint or back pain in a large patient population. DESIGN:Observational study. SETTING:US Medicare insurance claims data linked to rainfall data from US weather stations. PARTICIPANTS:1 552 842 adults aged ≥65 years attending a total of 11 673 392 outpatient visits with a general internist during 2008-12. MAIN OUTCOME MEASURES:The proportion of outpatient visits for joint or back pain related conditions (rheumatoid arthritis, osteoarthritis, spondylosis, intervertebral disc disorders, and other non-traumatic joint disorders) was compared between rainy days and non-rainy days, adjusting for patient characteristics, chronic conditions, and geographic fixed effects (thereby comparing rates of joint or back pain related outpatient visits on rainy days versus non-rainy days within the same area). RESULTS:Of the 11 673 392 outpatient visits by Medicare beneficiaries, 2 095 761 (18.0%) occurred on rainy days. In unadjusted and adjusted analyses, the difference in the proportion of patients with joint or back pain between rainy days and non-rainy days was significant (unadjusted, 6.23% 6.42% of visits, P<0.001; adjusted, 6.35% 6.39%, P=0.05), but the difference was in the opposite anticipated direction and was so small that it is unlikely to be clinically meaningful. No statistically significant relation was found between the proportion of claims for joint or back pain and the number of rainy days in the week of the outpatient visit. No relation was found among a subgroup of patients with rheumatoid arthritis. CONCLUSION:In a large analysis of older Americans insured by Medicare, no relation was found between rainfall and outpatient visits for joint or back pain. A relation may still exist, and therefore larger, more detailed data on disease severity and pain would be useful to support the validity of this commonly held belief. 10.1136/bmj.j5326
    Strategies for the prevention of knee osteoarthritis. Roos Ewa M,Arden Nigel K Nature reviews. Rheumatology Osteoarthritis (OA) has been thought of as a disease of cartilage that can be effectively treated surgically at severe stages with joint arthroplasty. Today, OA is considered a whole-organ disease that is amenable to prevention and treatment at early stages. OA develops slowly over 10-15 years, interfering with activities of daily living and the ability to work. Many patients tolerate pain, and many health-care providers accept pain and disability as inevitable corollaries of OA and ageing. Too often, health-care providers passively await final 'joint death', necessitating knee and hip replacements. Instead, OA should be viewed as a chronic condition, where prevention and early comprehensive-care models are the accepted norm, as is the case with other chronic diseases. Joint injury, obesity and impaired muscle function are modifiable risk factors amenable to primary and secondary prevention strategies. The strategies that are most appropriate for each patient should be identified, by selecting interventions to correct--or at least attenuate--OA risk factors. We must also choose the interventions that are most likely to be acceptable to patients, to maximize adherence to--and persistence with--the regimes. Now is the time to begin the era of personalized prevention for knee OA. 10.1038/nrrheum.2015.135
    Nerve Growth Factor and Pain Mechanisms. Denk Franziska,Bennett David L,McMahon Stephen B Annual review of neuroscience Nerve growth factor (NGF) antagonism is on the verge of becoming a powerful analgesic treatment for numerous conditions, including osteoarthritis and lower back pain. This review summarizes the historical research, both fundamental and clinical, that led to our current understanding of NGF biology. We also discuss the surprising number of questions that remain about NGF expression patterns and NGF's various functions and interaction partners in relation to persistent pain and the potential side effects of anti-NGF therapy. 10.1146/annurev-neuro-072116-031121
    Osteoarthritis: Pain variables differ in their associated markers. McHugh Jessica Nature reviews. Rheumatology 10.1038/nrrheum.2017.65
    The prevalence of radiographic and MRI-defined patellofemoral osteoarthritis and structural pathology: a systematic review and meta-analysis. Hart Harvi F,Stefanik Joshua J,Wyndow Narelle,Machotka Zuzana,Crossley Kay M British journal of sports medicine BACKGROUND:Patellofemoral osteoarthritis (PF OA) is more prevalent than previously thought and contributes to patient's suffering from knee OA. Synthesis of prevalence data can provide estimates of the burden of PF OA. OBJECTIVE:This study aims to conduct a systematic review and meta-analysis on the prevalence of PF OA and structural damage based on radiography and MRI studies in different populations. METHODS:We searched six electronic databases and reference lists of relevant cross-sectional and observational studies reporting the prevalence of PF OA. Two independent reviewers appraised methodological quality. Where possible, data were pooled using the following categories: radiography and MRI studies. RESULTS:Eighty-five studies that reported the prevalence of patellofemoral OA and structural damage were included in this systematic review. Meta-analysis revealed a high prevalence of radiographic PF OA in knee pain or symptomatic knee OA (43%), radiographic knee OA or at risk of developing OA (48%) and radiographic and symptomatic knee OA (57%) cohorts. The MRI-defined structural PF damage in knee pain or symptomatic population was 32% and 52% based on bone marrow lesion and cartilage defect, respectively. CONCLUSION:One half of people with knee pain or radiographic OA have patellofemoral involvement. Prevalence of MRI findings was high in symptomatic and asymptomatic population. These pooled data and the variability found can provide evidence for future research addressing risk factors and treatments for PF OA. TRIAL REGISTRATION NUMBER:PROSPERO systematic review protocol (CRD42016035649). 10.1136/bjsports-2017-097515
    Review: Some NSAIDs, notably diclofenac, improved knee or hip pain and function in osteoarthritis vs other NSAIDs. Schattner Ami Annals of internal medicine 10.7326/ACPJC-2016-165-2-009
    Establishing outcome measures in early knee osteoarthritis. Emery Carolyn A,Whittaker Jackie L,Mahmoudian Armaghan,Lohmander L Stefan,Roos Ewa M,Bennell Kim L,Toomey Clodagh M,Reimer Raylene A,Thompson Dylan,Ronsky Janet L,Kuntze Gregor,Lloyd David G,Andriacchi Thomas,Englund Martin,Kraus Virginia B,Losina Elena,Bierma-Zeinstra Sita,Runhaar Jos,Peat George,Luyten Frank P,Snyder-Mackler Lynn,Risberg May Arna,Mobasheri Ali,Guermazi Ali,Hunter David J,Arden Nigel K Nature reviews. Rheumatology The classification and monitoring of individuals with early knee osteoarthritis (OA) are important considerations for the design and evaluation of therapeutic interventions and require the identification of appropriate outcome measures. Potential outcome domains to assess for early OA include patient-reported outcomes (such as pain, function and quality of life), features of clinical examination (such as joint line tenderness and crepitus), objective measures of physical function, levels of physical activity, features of imaging modalities (such as of magnetic resonance imaging) and biochemical markers in body fluid. Patient characteristics such as adiposity and biomechanics of the knee could also have relevance to the assessment of early OA. Importantly, research is needed to enable the selection of outcome measures that are feasible, reliable and validated in individuals at risk of knee OA or with early knee OA. In this Perspectives article, potential outcome measures for early symptomatic knee OA are discussed, including those measures that could be of use in clinical practice and/or the research setting. 10.1038/s41584-019-0237-3
    How to be NICEr in treating osteoarthritis. Conaghan Philip G Nature reviews. Rheumatology 10.1038/s41584-018-0101-x
    Effectiveness of non-steroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: a network meta-analysis. da Costa Bruno R,Reichenbach Stephan,Keller Noah,Nartey Linda,Wandel Simon,Jüni Peter,Trelle Sven Lancet (London, England) BACKGROUND:Non-steroidal anti-inflammatory drugs (NSAIDs) are the backbone of osteoarthritis pain management. We aimed to assess the effectiveness of different preparations and doses of NSAIDs on osteoarthritis pain in a network meta-analysis. METHODS:For this network meta-analysis, we considered randomised trials comparing any of the following interventions: NSAIDs, paracetamol, or placebo, for the treatment of osteoarthritis pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the reference lists of relevant articles for trials published between Jan 1, 1980, and Feb 24, 2015, with at least 100 patients per group. The prespecified primary and secondary outcomes were pain and physical function, and were extracted in duplicate for up to seven timepoints after the start of treatment. We used an extension of multivariable Bayesian random effects models for mixed multiple treatment comparisons with a random effect at the level of trials. For the primary analysis, a random walk of first order was used to account for multiple follow-up outcome data within a trial. Preparations that used different total daily dose were considered separately in the analysis. To assess a potential dose-response relation, we used preparation-specific covariates assuming linearity on log relative dose. FINDINGS:We identified 8973 manuscripts from our search, of which 76 randomised trials with a total of 58 451 patients were included in this analysis. 23 nodes concerning seven different NSAIDs or paracetamol with specific daily dose of administration or placebo were considered. All preparations, irrespective of dose, improved point estimates of pain symptoms when compared with placebo. For six interventions (diclofenac 150 mg/day, etoricoxib 30 mg/day, 60 mg/day, and 90 mg/day, and rofecoxib 25 mg/day and 50 mg/day), the probability that the difference to placebo is at or below a prespecified minimum clinically important effect for pain reduction (effect size [ES] -0·37) was at least 95%. Among maximally approved daily doses, diclofenac 150 mg/day (ES -0·57, 95% credibility interval [CrI] -0·69 to -0·45) and etoricoxib 60 mg/day (ES -0·58, -0·74 to -0·43) had the highest probability to be the best intervention, both with 100% probability to reach the minimum clinically important difference. Treatment effects increased as drug dose increased, but corresponding tests for a linear dose effect were significant only for naproxen (p=0·034). We found no evidence that treatment effects varied over the duration of treatment. Model fit was good, and between-trial heterogeneity and inconsistency were low in all analyses. All trials were deemed to have a low risk of bias for blinding of patients. Effect estimates did not change in sensitivity analyses with two additional statistical models and accounting for methodological quality criteria in meta-regression analysis. INTERPRETATION:On the basis of the available data, we see no role for single-agent paracetamol for the treatment of patients with osteoarthritis irrespective of dose. We provide sound evidence that diclofenac 150 mg/day is the most effective NSAID available at present, in terms of improving both pain and function. Nevertheless, in view of the safety profile of these drugs, physicians need to consider our results together with all known safety information when selecting the preparation and dose for individual patients. FUNDING:Swiss National Science Foundation (grant number 405340-104762) and Arco Foundation, Switzerland. 10.1016/S0140-6736(17)31744-0
    Does This Patient Have Hip Osteoarthritis?: The Rational Clinical Examination Systematic Review. Metcalfe David,Perry Daniel C,Claireaux Henry A,Simel David L,Zogg Cheryl K,Costa Matthew L JAMA Importance:Hip osteoarthritis (OA) is a common cause of pain and disability. Objective:To identify the clinical findings that are most strongly associated with hip OA. Data Sources:Systematic search of MEDLINE, PubMed, EMBASE, and CINAHL from inception until November 2019. Study Selection:Included studies (1) quantified the accuracy of clinical findings (history, physical examination, or simple tests) and (2) used plain radiographs as the reference standard for diagnosing hip OA. Data Extraction and Synthesis:Studies were assigned levels of evidence using the Rational Clinical Examination scale and assessed for risk of bias using the Quality Assessment of Diagnostic Accuracy Studies tool. Data were extracted using individual hips as the unit of analysis and only pooled when findings were reported in 3 or more studies. Main Outcomes and Measures:Sensitivity, specificity, and likelihood ratios (LRs). Results:Six studies were included, with data from 1110 patients and 1324 hips, of which 509 (38%) showed radiographic evidence of OA. Among patients presenting to primary care physicians with hip or groin pain, the affected hip showed radiographic evidence of OA in 34% of cases. A family history of OA, personal history of knee OA, or pain on climbing stairs or walking up slopes all had LRs of 2.1 (sensitivity range, 33%-68%; specificity range, 68%-84%; broadest LR range: 95% CI, 1.1-3.8). To identify patients most likely to have OA, the most useful findings were squat causing posterior pain (sensitivity, 24%; specificity, 96%; LR, 6.1 [95% CI, 1.3-29]), groin pain on passive abduction or adduction (sensitivity, 33%; specificity, 94%; LR, 5.7 [95% CI, 1.6-20]), abductor weakness (sensitivity, 44%; specificity, 90%; LR, 4.5 [95% CI, 2.4-8.4]), and decreased passive hip adduction (sensitivity, 80%; specificity, 81%; LR, 4.2 [95% CI, 3.0-6.0]) or internal rotation (sensitivity, 66%; specificity, 79%; LR, 3.2 [95% CI, 1.7-6.0]) as measured by a goniometer or compared with the contralateral leg. The presence of normal passive hip adduction was most useful for suggesting the absence of OA (negative LR, 0.25 [95% CI, 0.11-0.54]). Conclusions and Relevance:Simple tests of hip motion and observing for pain during that motion were helpful in distinguishing patients most likely to have OA on plain radiography from those who will not. A combination of findings efficiently detects those most likely to have severe hip OA. 10.1001/jama.2019.19413
    Osteoarthritis. Hunter David J,Bierma-Zeinstra Sita Lancet (London, England) Osteoarthritis is a leading cause of disability and source of societal cost in older adults. With an ageing and increasingly obese population, this syndrome is becoming even more prevalent than in previous decades. In recent years, we have gained important insights into the cause and pathogenesis of pain in osteoarthritis. The diagnosis of osteoarthritis is clinically based despite the widespread overuse of imaging methods. Management should be tailored to the presenting individual and focus on core treatments, including self-management and education, exercise, and weight loss as relevant. Surgery should be reserved for those that have not responded appropriately to less invasive methods. Prevention and disease modification are areas being targeted by various research endeavours, which have indicated great potential thus far. This narrative Seminar provides an update on the pathogenesis, diagnosis, management, and future research on osteoarthritis for a clinical audience. 10.1016/S0140-6736(19)30417-9
    Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial. Kroon Féline P B,Kortekaas Marion C,Boonen Annelies,Böhringer Stefan,Reijnierse Monique,Rosendaal Frits R,Riyazi Naghmeh,Starmans Mirian,Turkstra Franktien,van Zeben Jende,Allaart Cornelia F,Kloppenburg Margreet Lancet (London, England) BACKGROUND:Hand osteoarthritis is a prevalent joint condition that has a high burden of disease and an unmet medical need for effective therapeutic options. Since local inflammation is recognised as contributing to osteoarthritic complaints, the Hand Osteoarthritis Prednisolone Efficacy (HOPE) study aimed to investigate the efficacy and safety of short-term prednisolone in patients with painful hand osteoarthritis and synovial inflammation. METHODS:The HOPE study is a double-blind, randomised, placebo-controlled trial. We recruited eligible adults from rheumatology outpatient clinics at two sites in the Netherlands. Patients were considered eligible if they had symptomatic hand osteoarthritis and signs of inflammation in their distal and proximal interphalangeal (DIP/PIP) joints. For inclusion, patients were required to have four or more DIP/PIP joints with osteoarthritic nodes; at least one DIP/PIP joint with soft swelling or erythema; at least one DIP/PIP joint with a positive power Doppler signal or synovial thickening of at least grade 2 on ultrasound; and finger pain of at least 30 mm on a 100-mm visual analogue scale (VAS) that flared up during a 48-h non-steroidal anti-inflammatory drug (NSAID) washout (defined as worsening of finger pain by at least 20 mm on the VAS). Eligible patients were randomly assigned (1:1) to receive 10 mg prednisolone or placebo orally once daily for 6 weeks, followed by a 2-week tapering scheme, and a 6-week follow-up without study medication. The patients and study team were masked to treatment assignment. The primary endpoint was finger pain, assessed on a VAS, at 6 weeks in participants who had been randomly assigned to groups and attended the baseline visit. This study is registered with the Netherlands Trial Registry, number NTR5263. FINDINGS:We screened patients for enrolment between Dec 3, 2015, and May 31, 2018. Patients completed baseline visits and started treatment between Dec 14, 2015, and July 2, 2018, and the last study visit of the last patient was Oct 4, 2018. Of 149 patients assessed for eligibility, 57 (38%) patients were excluded (predominantly because they did not meet one or several inclusion criteria, most often because of an absence of synovial inflammation or of flare-ups after NSAID washout) and 92 (62%) patients were eligible for inclusion. We randomly assigned 46 (50%) patients to receive prednisolone and 46 (50%) patients to receive placebo, all of whom were included in the modified intention-to-treat analysis of the primary endpoint. 42 (91%) patients in the prednisolone group and 42 (91%) in the placebo group completed the 14-week study. The mean change between baseline and week 6 on VAS-reported finger pain was -21·5 (SD 21·7) in the prednisolone group and -5·2 (24·3) in the placebo group, with a mean between-group difference (of prednisolone vs placebo) of -16·5 (95% CI -26·1 to -6·9; p=0·0007). The number of non-serious adverse events was similar between the groups. Five serious adverse events were reported during our study: one serious adverse event in the prednisolone group (a myocardial infarction) and four serious adverse events in the placebo group (an infected traumatic leg haematoma that required surgery, bowel surgery, atrial fibrillation that required a pacemaker implantation, and symptomatic uterine myomas that required a hysterectomy). Four (4%) patients discontinued the study because of an adverse event: one (2%) patient receiving prednisolone (for a myocardial infarction) and three (7%) patients receiving placebo (for surgery of the bowel and for an infected leg haematoma and for Lyme disease arthritis of the knee). INTERPRETATION:Treatment with 10 mg prednisolone for 6 weeks is efficacious and safe for the treatment of patients with painful hand osteoarthritis and signs of inflammation. The results of our study provide clinicians with a new short-term treatment option for patients with hand osteoarthritis who report a flare-up of their disease. FUNDING:Dutch Arthritis Society. 10.1016/S0140-6736(19)32489-4
    Senescent cells and osteoarthritis: a painful connection. Jeon Ok Hee,David Nathaniel,Campisi Judith,Elisseeff Jennifer H The Journal of clinical investigation Senescent cells (SnCs) are associated with age-related pathologies. Osteoarthritis is a chronic disease characterized by pain, loss of cartilage, and joint inflammation, and its incidence increases with age. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells' relevance to disease was unclear. In this Review, we summarize current knowledge of SnCs in the multiple tissues that constitute the articular joint. New evidence for the causative role of SnCs in the development of posttraumatic and age-related arthritis is reviewed along with the therapeutic benefit of SnC clearance. As part of their senescence-associated secretory phenotype, SnCs secrete cytokines that impact the immune system and its response to joint tissue trauma. We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis. 10.1172/JCI95147
    Association of Pharmacological Treatments With Long-term Pain Control in Patients With Knee Osteoarthritis: A Systematic Review and Meta-analysis. Gregori Dario,Giacovelli Giampaolo,Minto Clara,Barbetta Beatrice,Gualtieri Francesca,Azzolina Danila,Vaghi Paola,Rovati Lucio C JAMA Importance:Even though osteoarthritis is a chronic and progressive disease, pharmacological agents are mainly studied over short-term periods, resulting in unclear recommendations for long-term disease management. Objective:To search, review, and analyze long-term (≥12 months) outcomes (symptoms, joint structure) from randomized clinical trials (RCTs) of medications for knee osteoarthritis. Data Sources and Study Selection:The databases of MEDLINE, Scopus, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials were searched until June 30, 2018 (MEDLINE alerts through August 31, 2018) for RCTs of patients with knee osteoarthritis that had treatment and follow-up lasting 1 year or longer. Data Extraction and Synthesis:Data at baseline and at the longest available treatment and follow-up of 12 months' duration or longer (or the change from baseline) were extracted. A Bayesian random-effects network meta-analysis was performed. Main Outcomes and Measures:The primary outcome was the mean change from baseline in knee pain. Secondary outcomes were physical function and joint structure (the latter was measured radiologically as joint space narrowing). Standardized mean differences (SMDs) and mean differences with 95% credibility intervals (95% CrIs) were calculated. Findings were interpreted as associations when the 95% CrIs excluded the null value. Results:Forty-seven RCTs (22 037 patients; mean age range, mostly 55-70 years; and a higher mean proportion of women than men, around 70%) included the following medication categories: analgesics; antioxidants; bone-acting agents such as bisphosphonates and strontium ranelate; nonsteroidal anti-inflammatory drugs; intra-articular injection medications such as hyaluronic acid and corticosteroids; symptomatic slow-acting drugs in osteoarthritis such as glucosamine and chondroitin sulfate; and putative disease-modifying agents such as cindunistat and sprifermin. Thirty-one interventions were studied for pain, 13 for physical function, and 16 for joint structure. Trial duration ranged from 1 to 4 years. Associations with decreases in pain were found for the nonsteroidal anti-inflammatory drug celecoxib (SMD, -0.18 [95% CrI, -0.35 to -0.01]) and the symptomatic slow-acting drug in osteoarthritis glucosamine sulfate (SMD, -0.29 [95% CrI, -0.49 to -0.09]), but there was large uncertainty for all estimates vs placebo. The association with pain improvement remained significant only for glucosamine sulfate when data were analyzed using the mean difference on a scale from 0 to 100 and when trials at high risk of bias were excluded. Associations with improvement in joint space narrowing were found for glucosamine sulfate (SMD, -0.42 [95% CrI, -0.65 to -0.19]), chondroitin sulfate (SMD, -0.20 [95% CrI, -0.31 to -0.07]), and strontium ranelate (SMD, -0.20 [95% CrI, -0.36 to -0.05]). Conclusions and Relevance:In this systematic review and network meta-analysis of studies of patients with knee osteoarthritis and at least 12 months of follow-up, there was uncertainty around the estimates of effect size for change in pain for all comparisons with placebo. Larger RCTs are needed to resolve the uncertainty around efficacy of medications for knee osteoarthritis. 10.1001/jama.2018.19319
    Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period. Berenbaum Francis,Blanco Francisco J,Guermazi Ali,Miki Kenji,Yamabe Takaharu,Viktrup Lars,Junor Rod,Carey William,Brown Mark T,West Christine R,Verburg Kenneth M Annals of the rheumatic diseases OBJECTIVE:Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up. METHODS:This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.5 mg or 5 mg subcutaneously or matching placebo every 8 weeks (three doses). Co-primary end points were change from baseline to week 24 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Physical Function, and Patient's Global Assessment of OA (PGA-OA). Joint safety and neurological assessments continued throughout the 48-week study. RESULTS:From March 2016 to December 2017, 849 patients were randomised and evaluated (placebo n=282, tanezumab 2.5 mg n=283, tanezumab 5 mg n=284). At week 24, there was a statistically significant improvement from baseline for tanezumab 5 mg compared with placebo for WOMAC Pain (least squares mean difference±SE -0.62±0.18, p=0.0006), WOMAC Physical Function (-0.71±0.17, p<0.0001) and PGA-OA (-0.19±0.07, p=0.0051). For tanezumab 2.5 mg, there was a statistically significant improvement in WOMAC Pain and Physical Function, but not PGA-OA. Rapidly progressive osteoarthritis (RPOA) was observed in 1.4% (4/283) and 2.8% (8/284) of patients in the tanezumab 2.5 mg and tanezumab 5 mg groups, respectively and none receiving placebo. Total joint replacements (TJRs) were similarly distributed across all three treatment groups (6.7%-7.8%). Tanezumab-treated patients experienced more paraesthesia (5 mg) and hypoaesthesia (both doses) than placebo. CONCLUSION:Tanezumab 5 mg statistically significantly improved pain, physical function and PGA-OA, but tanezumab 2.5 mg only achieved two co-primary end points. RPOA occurred more frequently with tanezumab 5 mg than tanezumab 2.5 mg. TJRs were similarly distributed across all three groups. TRIAL REGISTRATION NUMBER:NCT02709486. 10.1136/annrheumdis-2019-216296
    Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies. Zeng Chao,Wei Jie,Persson Monica S M,Sarmanova Aliya,Doherty Michael,Xie Dongxing,Wang YiLun,Li Xiaoxiao,Li Jiatian,Long Huizhong,Lei Guanghua,Zhang Weiya British journal of sports medicine OBJECTIVES:To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA). METHODS:PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies. RESULTS:43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=-0.30, 95% CI -0.40 to -0.20) and improving function (SMD=-0.35, 95% CI -0.45 to -0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=-0.81, 95% CI -1.12 to -0.52) and piroxicam was most effective for functional improvement (SMD=-1.04, 95% CI -1.60 to -0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs. CONCLUSIONS:Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study. 10.1136/bjsports-2017-098043