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The effects of exercise on synovitis and bone marrow lesions in knee osteoarthritis: secondary outcomes from a randomized controlled trial

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  • University of Copenhagen, Bispebjerg and Frederiksberg Hospital
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Knee osteoarthritis (OA) is believed to be highly prevalent today because of recent increases in life expectancy and body mass index (BMI), but this assumption has not been tested using long-term historical or evolutionary data. We analyzed long-term trends in knee OA prevalence in the United States using cadaver-derived skeletons of people aged ≥50 y whose BMI at death was documented and who lived during the early industrial era (1800s to early 1900s; n = 1,581) and the modern postindustrial era (late 1900s to early 2000s; n = 819). Knee OA among individuals estimated to be ≥50 y old was also assessed in archeologically derived skeletons of prehistoric hunter-gatherers and early farmers (6000–300 B.P.; n = 176). OA was diagnosed based on the presence of eburnation (polish from bone-on-bone contact). Overall, knee OA prevalence was found to be 16% among the postindustrial sample but only 6% and 8% among the early industrial and prehistoric samples, respectively. After controlling for age, BMI, and other variables, knee OA prevalence was 2.1-fold higher (95% confidence interval, 1.5–3.1) in the postindustrial sample than in the early industrial sample. Our results indicate that increases in longevity and BMI are insufficient to explain the approximate doubling of knee OA prevalence that has occurred in the United States since the mid-20th century. Knee OA is thus more preventable than is commonly assumed, but prevention will require research on additional independent risk factors that either arose or have become amplified in the postindustrial era.
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Background Braces are used to treat pain in patellofemoral joint osteoarthritis (PFJOA). In a trial, we previously reported pain improvement after 6-weeks brace use. The pain reduction did not correlate with changes in Magnetic Resonance Imaging (MRI) assessed Bone Marrow Lesion volume or static synovial volume. Studies show that changes in the synovium on dynamic contrast enhanced (DCE) MRI are more closely associated with symptom change than static synovial volume changes. We hypothesised change in synovitis assessed using dynamic imaging could explain the reduction in pain. Method One hundred twenty-six men and women aged 40–70 years with painful radiographically confirmed PFJOA were randomised to either brace wearing or no brace for 6-weeks. Pain assessment and DCE-MRI were performed at baseline and 6 weeks. DCE data was analysed using Tofts’s equation. Pain measures included a VAS of pain on nominated aggravating activity (VASNA), and the KOOS pain subscale. Paired t-tests were used to determine within person change in outcome measures and Spearman’s correlation coefficients were used to determine the correlation between change in pain and change in the DCE parameters. ResultsMean age of subjects was 55.5 years (SD = 7.5) and 57% were female. There was clear pain improvement in the brace users compared to controls (VASNA − 16.87 mm, p = <0.001). There was no significant change to the dynamic synovitis parameters among brace users nor was pain change correlated with change in dynamic synovitis parameters. Conclusion The reduction in knee pain following brace wearing in patients with PFJOA is not explained by changes in synovitis. Trial registrationTrial registration number UK. ISRCTN50380458/Registered 21.5.2010.
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Objective: Painful knee osteoarthritis (KOA) has been associated with joint inflammation. There is, however, little literature correlating signs of localized inflammation with contrast-enhanced (CE) magnetic resonance imaging (MRI) of synovium. This study examined the relationship between clinical and functional markers of localized knee inflammation and CE MRI-based synovial scores. Methods: Patients with symptomatic KOA were enrolled into the randomized, double-blind, Vitamin D Evaluation in Osteoarthritis (VIDEO) trial. In this cross-sectional substudy, associations between validated MRI-based semiquantitative synovial scores of the knee and the following markers of inflammation were investigated: self-reported pain and stiffness, effusion, warmth, joint line tenderness, erythrocyte sedimentation rate, radiographic severity, and functional ability tests. Results: A total of 107 patients satisfied the inclusion criteria of complete data and were included in the analysis. Significant associations were found between the number of regions affected by synovitis and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, effusion, and joint line tenderness. Each additional region affected by synovitis was associated with an increase in WOMAC pain (1.82 [95% confidence interval (95% CI) 0.05, 3.58], P = 0.04), and the association with extent of medial synovitis was particularly strong (3.21 [95% CI 0.43, 5.99], P = 0.02). Extent of synovitis was positively associated with effusion (odds ratio 1.69 [95% CI 1.37, 2.08], P < 0.01) and negatively associated with joint line tenderness (relative risk 0.87 [95% CI 0.84, 0.90], P < 0.01). Conclusion: There is a strong positive association between synovitis and self-reported patient pain and clinically detectable effusion. Nonoperative treatments directed at management of inflammation and future trials targeting the synovial tissue for treating KOA should consider these 2 factors as potential inclusion criteria.
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Background Bone marrow lesions (BMLs) in knee osteoarthritis (OA) can be assessed using fluid sensitive and contrast enhanced sequences. The association between BMLs and symptoms has been investigated in several studies but only using fluid sensitive sequences. Our aims were to assess BMLs by contrast enhanced MRI sequences in comparison with a fluid sensitive STIR sequence using two different segmentation methods and to analyze the association between the MR findings and disability and pain. Methods Twenty-two patients (mean age 61 years, range 41–79 years) with medial femoro-tibial knee OA obtained MRI and filled out a WOMAC questionnaire at baseline and follow-up (median interval of 334 days). STIR, dynamic contrast enhanced-MRI (DCE-MRI) and fat saturated T1 post-contrast (T1 CE FS) MRI sequences were obtained. All STIR and T1 CE FS sequences were assessed independently by two readers for STIR-BMLs and contrast enhancing areas of BMLs (CEA-BMLs) using manual segmentation and computer assisted segmentation, and the measurements were compared. DCE-MRIs were assessed for the relative distribution of voxels with an inflammatory enhancement pattern, Nvoxel, in the bone marrow. All findings were compared to WOMAC scores, including pain and overall symptoms, and changes from baseline to follow-up were analyzed. ResultsThe average volume of CEA-BML was smaller than the STIR-BML volume by manual segmentation. The opposite was found for computer assisted segmentation where the average CEA-BML volume was larger than the STIR-BML volume. The contradictory finding by computer assisted segmentation was partly caused by a number of outliers with an apparent generally increased signal intensity in the anterior parts of the femoral condyle and tibial plateau causing an overestimation of the CEA-BML volume.Both CEA-BML, STIR-BML and Nvoxel were significantly correlated with symptoms and to a similar degree. A significant reduction in total WOMAC score was seen at follow-up, but no significant changes were observed for either CEA-BML, STIR-BML or Nvoxel. Conclusions Neither the degree nor the volume of contrast enhancement in BMLs seems to add any clinical information compared to BMLs visualized by fluid sensitive sequences. Manual segmentation may be needed to obtain valid CEA-BML measurements.
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Purpose of review: Inflammatory changes in joint tissues can be detected by modern imaging techniques in osteoarthritis patients, but may be clinically subtle compared with many other types of arthritis. These changes associate with disease progression and clinical severity, and many inflammatory mediators may have biomarker utility. Moreover, a number of inflammatory mechanisms play a role in animal models of disease, but it is still not clear which mechanisms predominate and might be therapeutically manipulated most effectively. This review highlights specific examples of recent advances published in the past 18 months that have advanced this field. Recent findings: Clinical investigators now show that synovial inflammation is associated with pain sensitization, and similar to knee osteoarthritis, is a common and important feature of hand osteoarthritis. In addition, recent advances in basic studies demonstrate inflammatory markers and mechanisms related to leukocyte activity, innate immune mechanisms, and the chondrocyte-intrinsic inflammatory response that might provide better opportunities for early detection, prognosis, or therapeutic intervention. Summary: Inflammation plays a central role in osteoarthritis pathogenesis, but additional translational work in this field is necessary, as are more clinical trials of anti-inflammatory approaches.
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Objective: To investigate the course of synovitis on contrast-enhanced MRI in osteoarthritic knees over 2 years, and its association with pain and cartilage deterioration. Design: Consecutive patients (n=39, mean age 61 years, 79% woman, median (range) BMI 29 (24-48) kg/mm(2)) with clinical OA were included. Baseline and follow-up contrast-enhanced MR images (3T) were scored paired in chronological order for synovitis (semi-quantitatively at 11 sites (range 0-22)), cartilage deterioration and bone marrow lesions (BML) (semi-quantitatively according to KOSS). Changes in sum scores were calculated. Cartilage deterioration was defined as change of ≥ 2 above the smallest detectable change (SDC). Pain was assessed by standardized questionnaires. ANCOVA and linear regression models were used to investigate association between synovitis change and cartilage deterioration and between synovitis change or cartilage deterioration and change in pain. Results: The total synovitis score did not change over 2 years (mean change 0.2 (SD 3.2), although changes in individual patients were observed. Cartilage deterioration was observed in 51% of patients. Synovitis change score was lower in patients without compared to patients with cartilage deterioration, taking BML change in account (mean difference -2.1(-4.1- -0.1)). Change in synovitis was not associated with change in pain, whereas cartilage deterioration was associated with change in ICOAP constant pain in adjusted models (Β (95%CI) 2.8 (0.4-5.3)). Conclusions: In individual patients synovitis fluctuates during disease course. Synovitis change was not associated with change in pain. Increase in synovitis is associated with cartilage deterioration, suggesting a role for synovitis as a target for disease-modifying treatment.
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Background Previous studies showed that among persons with radiographic knee OA, periarticular lesions were significantly more common among participants with knee pain than those without. However, data were derived mostly from persons with knee OA, and there were few normal participants without knee OA in the data analyses. The objectives of this study were to investigate the prevalence of periarticular lesions detected by magnetic resonance imaging (MRI), and to examine their prevalence according to the presence of knee pain and radiographic knee osteoarthritis (OA) in community residents in Korea. Methods Demographic and knee pain data were obtained by questionnaire from 358 participants of the population-based Hallym Aging Study who were recruited irrespective of the presence of knee OA or pain. Radiographic evaluations consisted of weight-bearing knee anteroposterior radiographs and 1.5-T MRI scans. Periarticular lesions included prepatellar or anserine bursitis, Baker’s cyst, and tibiofibular cyst. The prevalence of each lesion in subjects with knee OA or knee pain compared to those without was examined by a chi-square test. ResultsThe mean age of the subjects was 72 years and 50.6 % were female. Radiographic knee OA was present in 34.5 %. The most prevalent peri-articular lesion was Baker’s cyst (27.9 %), followed by tibiofibular cyst (9.5 %). Anserine bursitis and tibulofibular cyst were more common in subjects with knee OA (17.5 % vs 2.2 % for anserine bursitis, 15.8 % vs 6.1 % for tibiofibular cyst in subjects with and without OA, respectively), while Baker’s cyst and anserine bursitis were more common in subjects with knee pain (36.3 % vs 21.8 % for Baker’s cyst, 14.4 % vs 2.5 % for anserine bursitis in subjects with and without knee pain, respectively). Conclusions Periarticular lesions on MRI of the knee are common in middle-aged and elderly persons. Anserine bursitis and Baker’s cysts are more common in subjects with knee pain compared to those without.
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Objective: To determine the association between changes in semi-quantitative knee MRI biomarkers over 24 months and radiographic and pain progression over 48 months in knees with mild to moderate osteoarthritis. Methods: We undertook a nested case-control study as part of the Osteoarthritis Biomarkers Consortium Project. We built multivariable logistic regression models to examine the association between change over 24 months in semi-quantitative MR imaging markers and knee OA radiographic and pain progression. MRIs were read according to the MRI Osteoarthritis Knee Score (MOAKS) scoring system. We focused on changes in cartilage, osteophytes, meniscus, bone marrow lesions, Hoffa-synovitis, and synovitis-effusion. Results: The most parsimonious model included changes in cartilage thickness and surface area, synovitis-effusion, Hoffa-synovitis, and meniscal morphology (C-statistic =0.740). Subjects with worsening cartilage thickness in 3+ subregions vs. no worsening had 2.8-fold (95% CI: 1.3 - 5.9) greater odds of being a case while subjects with worsening in cartilage surface area in 3+ subregions vs. no worsening had 2.4-fold (95% CI: 1.3 - 4.4) greater odds of being a case. Having worsening in any region in meniscal morphology was associated with a 2.2-fold (95%CI: 1.3 - 3.8) greater odds of being a case. Worsening synovitis-effusion (OR=2.7) and Hoffa-synovitis (OR=2.0) were also associated with greater odds of being a case. Conclusion: Twenty-four-month change in cartilage thickness, cartilage surface area, synovitis-effusion, Hoffa-synovitis, and meniscal morphology were independently associated with OA progression, suggesting that they may serve as efficacy biomarkers in clinical trials of disease modifying interventions for knee OA. This article is protected by copyright. All rights reserved.
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Objective: Synovium is increasingly a target of osteoarthritis (OA) treatment, yet its optimal measurement is unclear. Using dynamic contrast enhanced (DCE) MRI in knee OA patients before and after intraarticular steroid injection, we compared the responsiveness of static synovial volume measures to measures of dynamic changes in synovial enhancement, changes that are strongly related to synovial vascularity. Methods: 93 patients underwent DCE-MRI before and 1-2 weeks after intra-articular injection of 80mg methylprednisolone. Synovium was segmented and volume, relative enhancement rate (RER), maximum relative enhancement (REmax), late relative enhancement (RElate) and pharmacokinetic parameters (K(trans), ve) were calculated. KOOS pain score was recorded before and after injection. Standardized change scores were calculated for each parameter. Linear regression and Pearson's correlations were used to investigate the relationship between change in MRI parameters and change in pain. Results: The change in standardized score for the measures of synovial enhancement, RElate and REmax were -0.58 (95% CI -0.79 to -0.37) and -0.62 (95% CI -0.83 to -0.41) respectively, whereas the score for synovial volume was -0.30 (-0.52 to -0.09). Further, change in knee pain correlated more strongly with changes in enhancement (for both REmax and RElate, r = -0.27 (95% CI -0.45 to -0.07)) than with changes in synovial volume -0.15 (-0.35 to 0.05). Conclusion: This study suggests DCE-MRI derived measures of synovial enhancement may be more sensitive to the response to treatment and more strongly associated with changes in pain than synovial volume and may be better outcomes for assessment of structural effects of treatment in OA.
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Objective: The prevalence of symptomatic knee osteoarthritis (OA) has been increasing over the past several decades in the United States concurrent with an aging population and the growing obesity epidemic. We quantify the impact of these factors on the number of persons with symptomatic knee OA in the first decades of 21st century. Methods: We calculated prevalence of clinically diagnosed symptomatic knee OA from the National Health Interview Survey 2007-08 and derived the proportion with advanced disease (Kellgren-Lawrence grades 3-4) using the Osteoarthritis Policy Model, a validated simulation model of knee OA. Incorporating contemporary obesity rates and population estimates, we calculated the number of persons living with symptomatic knee OA. Results: We estimate that about fourteen million persons had symptomatic knee OA, with advanced OA comprising over half of those cases. This includes over three million African American, Hispanic, and other racial/ethnic minorities. Adults under 45 years of age represented nearly two million cases of symptomatic knee OA and individuals between 45 and 65 years of age six million more. Conclusion: Over half of all persons with symptomatic knee OA are younger than 65 years of age. As many of these younger persons will live for three decades or more, there is substantially more time for greater disability to occur and policymakers should anticipate healthcare utilization for knee OA to increase further in upcoming decades. These data emphasize the need for the deployment of innovative prevention and treatment strategies for knee OA, especially among younger persons. This article is protected by copyright. All rights reserved.
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Objective: To get a better understanding of inflammatory pathways active in the osteoarthritic (OA) joint, we characterized and compared inflammatory cells in the synovium and the infrapatellar fat pad (IFP) of patients with knee OA. Methods: Infiltrating immune cells were characterized by flow cytometry in 76 patients with knee OA (mean age 63.3, 52% women, median body mass index 28.9) from whom synovial tissue (n = 40) and IFP (n = 68) samples were obtained. Pain was assessed by the visual analog scale (VAS; 0-100 mm). Spearman rank correlations and linear regression analyses adjusted for sex and age were performed. Results: Macrophages and T cells, followed by mast cells, were the most predominant immune cells in the synovium and IFP, and were equally abundant in these tissues. Macrophages and T cells secreted mostly proinflammatory cytokines even without additional stimulation, indicating their activated state. Accordingly, most CD4+ T cells had a memory phenotype and contained a significant population of cells expressing activation markers (CD25+, CD69+). Interestingly, the percent of CD69+ T cells was higher in synovial than IFP CD4+ T cells. Preliminary analyses indicated that the number of synovial CD4+ T cells were associated with VAS pain (β 0.51, 95% CI 0.09-1.02, p = 0.02). Conclusion: Our data suggest that the immune cell composition of the synovium and the IFP is similar, and includes activated cells that could contribute to inflammation through secretion of proinflammatory cytokines. Moreover, preliminary analyses indicate that synovial CD4+ T cells might associate with pain in patients with endstage OA of the knee.
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[Purpose] The aim of this study was to examine the effects of exercise therapy on the health-related QOL of people with knee osteoarthritis. [Subjects] Four databases (PubMed, Cochrane Central Register of Controlled Trials, the Physiotherapy Evidence Database, and the Cumulative Index to Nursing and Allied Health Literature) were searched for randomized controlled trials that evaluated the effects of exercise therapy on health-related QOL assessed by the SF-36 for inclusion in our systematic review. The methodological qualities of the trials were assessed independently by two reviewers using the PEDro scale. Pooled analyses with a random-effects model or a fixed-effects model were used in the meta-analyses to calculate the standardized mean differences and 95% confidence intervals. [Results] Twelve studies met the inclusion criteria. Our meta-analysis provides high-quality evidence that exercise therapy increases the summary score, physical functioning score, and role-physical score of knee osteoarthritis sufferers. Our meta-analysis also provides moderate-quality evidence that the physical component summary and mental component summary scores were improved to a greater extent by exercise therapy than by control interventions. [Conclusion] Exercise therapy can improve health-related QOL, as assessed by the SF-36, of knee osteoarthritis sufferers.
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Objective: Pain sensitization is associated with pain severity in knee osteoarthritis, but its cause in humans is not well-understood. We examined whether inflammation, assessed as synovitis and effusion on MRI, or mechanical load, assessed as bone marrow lesions (BMLs), were associated with sensitization in knee osteoarthritis. Methods: Subjects in the Multicenter Osteoarthritis Study, a NIH-funded cohort of persons with or at risk of knee osteoarthritis, had knee radiographs and MRIs, and standardized quantitative sensory testing (QST) measures (temporal summation, pressure pain threshold (PPT)) at the wrist and patellae obtained at baseline and two years later. We examined the relation of synovitis, effusion, and BMLs to temporal summation and PPT cross-sectionally and longitudinally. Results: There were 1111 subjects in the study sample (mean age 67, mean BMI 30, 62% female). Synovitis was associated with a significant decrease in PPT at the patella (i.e., more sensitized) over two years (adjusted beta: -0.30, 95% CI -0.52 to -0.08). Effusion was similarly associated with a decrease in PPT at the wrist (-0.24, 95% CI -0.41 to -0.24) and with risk of incident temporal summation (adjusted OR 1.54, 95% CI 1.01-2.36). BMLs were not associated with either QST measure. Conclusion: Inflammation, as evidenced by synovitis or effusion, is associated with pain sensitization in knee osteoarthritis. In contrast, BMLs do not appear to contribute to sensitization in knee osteoarthritis. Early targeting of inflammation is a reasonable strategy to test for prevention of sensitization and through this, reduction of pain severity in knee osteoarthritis. This article is protected by copyright. All rights reserved.
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Objective: To identify the independent relation of synovitis with incident radiographic knee osteoarthritis (OA) after adjusting for other structural factors known to cause synovitis. Design: We examined MRIs from knees that developed incident radiographic OA from the Multicenter Osteoarthritis Study (MOST) and compared these case knees with controls that did not develop OA. We examined baseline MRIs for knees developing OA at any time up to 84 months follow-up. We scored lesions in cartilage, meniscus, bone marrow and synovitis. Synovitis scores were summed (0-9) across 3 regions, suprapatellar, infrapatellar and intercondylar region, each of which was scored 0-3. After bivariate analyses examining each factor's association with incidence, we carried out multivariable regression analyses adjusting for age, sex, BMI, alignment and cartilage and meniscal damage. Results: We studied 239 case and 731 control knees. In bivariate analyses, cartilage lesions, meniscal damage, synovitis and bone marrow lesions were all risk factors for OA. After multivariable analyses, synovitis was associated with incident OA. A higher synovitis score increased the risk of incident OA (adjusted OR per unit increase 1.1; (95% CI 1.0, 1.2, p=.02), but increased risk was associated only with synovitis scores of >=3 (adjusted OR 1.6; 95% CI 1.2, 2.1, p = .003) CONCLUSIONS: Synovitis, especially when there is a substantial volume within the knee, is an independent cause of OA.
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Objective: To determine whether land-based therapeutic exercise is beneficial for people with knee osteoarthritis (OA) in terms of reduced joint pain or improved physical function and quality of life. Methods: Five electronic databases were searched, up until May 2013. Randomised clinical trials comparing some form of land-based therapeutic exercise with a non-exercise control were selected. Three teams of two review authors independently extracted data and assessed risk of bias for each study. Standardised mean differences immediately after treatment and 2-6 months after cessation of formal treatment were separately pooled using a random effects model. Results: In total, 54 studies were identified. Overall, 19 (35%) studies reported adequate random sequence generation, allocation concealment and adequately accounted for incomplete outcome data. However, research results may be vulnerable to selection, attrition and detection bias. Pooled results from 44 trials indicated that exercise significantly reduced pain (12 points/100; 95% CI 10 to 15) and improved physical function (10 points/100; 95% CI 8 to 13) to a moderate degree immediately after treatment, while evidence from 13 studies revealed that exercise significantly improved quality of life immediately after treatment with small effect (4 points/100; 95% CI 2 to 5). In addition, 12 studies provided 2-month to 6-month post-treatment sustainability data which showed significantly reduced knee pain (6 points/100; 95% CI 3 to 9) and 10 studies which showed improved physical function (3 points/100; 95% CI 1 to 5). Conclusions: Among people with knee osteoarthritis, land-based therapeutic exercise provides short-term benefit that is sustained for at least 2-6 months after cessation of formal treatment.
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To introduce the most popular magnetic resonance imaging (MRI) osteoarthritis (OA) semi-quantitative (SQ) scoring systems to a broader audience with a focus on the most commonly applied scores, i.e. the MOAKS and WORMS system and illustrate similarities and differences. While the main structure and methodology of each scoring system are publicly available, the core of this overview will be an illustrative imaging atlas section including image examples from multiple osteoarthritis studies applying MRI in regard to different features assessed, show specific examples of different grades and point out pitfalls and specifics of SQ assessment including artifacts, blinding to time point of acquisition and within-grade evaluation. Similarities and differences between different scoring systems are presented. Technical considerations are followed by a brief description of the most commonly utilized SQ scoring systems including their responsiveness and reliability. The second part is comprised of the atlas section presenting illustrative image examples. Evidence suggests that SQ assessment of OA by expert MRI readers is valid, reliable and responsive, which helps investigators to understand the natural history of this complex disease and to evaluate potential new drugs in OA clinical trials. Researchers have to be aware of the differences and specifics of the different systems to be able to engage in imaging assessment and interpretation of imaging-based data. SQ scoring has enabled us to explain associations of structural tissue damage with clinical manifestations of the disease and with morphological alterations thought to represent disease progression. Copyright © 2015. Published by Elsevier Ltd.
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Synovitis occurring frequently in osteoarthritis (OA) may be a targeted outcome. There are no data examining whether synovitis changes following intra-articular intervention. Persons aged 40 years and older with painful knee OA participated in an open label trial of intra-articular steroid therapy. At all time points they completed the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire. They had a contrast-enhanced (CE) MRI immediately prior to an intra-articular steroid injection with a repeat scan within 20 days. Response status was assessed using the Osteoarthritis Research Society International (OARSI) response criteria. OARSI responders were followed until their pain relapsed either within 20% of baseline or 6 months, shortly after which a third MRI was performed. Synovial tissue volume (STV) was measured on postcontrast knee images. We looked at changes in the STV and in pain, and their association. 120 subjects with preinjection and postinjection CE MRI were followed. Their mean age was 62.3 years (SD=10.3) and 62 (52%) were women. The median time between injection and follow-up scan was 8 days (IQR 7-14 days). 85/120 (71%) were OARSI responders. Pain decreased (mean change in KOOS=+23.9; 95% CI 20.1 to 27.8, p<0.001) following steroid injection, as did mean STV (mean change=-1071 mm(3); 95% CI -1839 mm(3) to -303 mm(3), p=0.01). Of the 80 who returned for a third MRI, pain relapsed in 57, and in the 48 of those with MRI data, STV increased between follow-up and final visit (+1220 mm(3); 95% CI 25 mm(3) to 2414 mm(3), p=0.05). 23 were persistent responders at 6 months and, in these, STV did not increase (mean change=-202 mm(3); 95% CI -2008 mm(3) to 1604 mm(3), p=0.83). Controlling for variation over time, there was a significant association between synovitis volume and KOOS pain (b coefficient-change in KOOS pain score per 1000 mm(3) change in STV=-1.13; 95% CI -1.87 to -0.39, p=0.003), although STV accounted for only a small proportion of the variance in change in pain. Synovial tissue volume in knee OA shrinks following steroid therapy, and rebounds in those whose pain relapses. It can be considered a treatment target in symptomatic knee OA. ISRCTN07329370. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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To investigate the efficacy and safety of paracetamol (acetaminophen) in the management of spinal pain and osteoarthritis of the hip or knee. Systematic review and meta-analysis. Medline, Embase, AMED, CINAHL, Web of Science, LILACS, International Pharmaceutical Abstracts, and Cochrane Central Register of Controlled Trials from inception to December 2014. Randomised controlled trials comparing the efficacy and safety of paracetamol with placebo for spinal pain (neck or low back pain) and osteoarthritis of the hip or knee. Two independent reviewers extracted data on pain, disability, and quality of life. Secondary outcomes were adverse effects, patient adherence, and use of rescue medication. Pain and disability scores were converted to a scale of 0 (no pain or disability) to 100 (worst possible pain or disability). We calculated weighted mean differences or risk ratios and 95% confidence intervals using a random effects model. The Cochrane Collaboration's tool was used for assessing risk of bias, and the GRADE approach was used to evaluate the quality of evidence and summarise conclusions. 12 reports (13 randomised trials) were included. There was "high quality" evidence that paracetamol is ineffective for reducing pain intensity (weighted mean difference -0.5, 95% confidence interval -2.9 to 1.9) and disability (0.4, -1.7 to 2.5) or improving quality of life (0.4, -0.9 to 1.7) in the short term in people with low back pain. For hip or knee osteoarthritis there was "high quality" evidence that paracetamol provides a significant, although not clinically important, effect on pain (-3.7, -5.5 to -1.9) and disability (-2.9, -4.9 to -0.9) in the short term. The number of patients reporting any adverse event (risk ratio 1.0, 95% confidence interval 0.9 to 1.1), any serious adverse event (1.2, 0.7 to 2.1), or withdrawn from the study because of adverse events (1.2, 0.9 to 1.5) was similar in the paracetamol and placebo groups. Patient adherence to treatment (1.0, 0.9 to 1.1) and use of rescue medication (0.7, 0.4 to 1.3) was also similar between groups. "High quality" evidence showed that patients taking paracetamol are nearly four times more likely to have abnormal results on liver function tests (3.8, 1.9 to 7.4), but the clinical importance of this effect is uncertain. Paracetamol is ineffective in the treatment of low back pain and provides minimal short term benefit for people with osteoarthritis. These results support the reconsideration of recommendations to use paracetamol for patients with low back pain and osteoarthritis of the hip or knee in clinical practice guidelines. PROSPERO registration number CRD42013006367. © Machado et al 2015.
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The role of skeletal muscle in the pathophysiology of knee OA is poorly understood. To date, the majority of literature has focused on the association of muscle strength with OA symptoms, disease onset and progression. However, deficits or improvements in skeletal muscle strength do not fully explain the mechanisms behind outcome measures in knee OA, such as pain, function and structural disease. This review aims to summarize components of skeletal muscle, providing a holistic view of skeletal muscle mechanisms that includes muscle function, quality and composition and their interactions. Similarly, the role of skeletal muscle in the management of knee OA will be discussed.
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Osteoarthritis (OA) is the most common form of arthritis, with knee OA itself being among the most common conditions and a leading cause of disability among older adults worldwide. Pain is a key symptom in the decision to seek medical attention, yet available therapies for managing OA are limited with only minimal or moderate efficacy. Current approaches to pain management in OA have been rather non-specific, limited to acetaminophen or NSAIDs primarily, without targeting underlying structural lesions that may be contributing to pain in OA. With the advent of MRI, a number of studies have noted the importance of bone marrow lesions and synovitis/effusion to the pain experience in OA. These pathologic features are therefore attractive treatment targets, with some proof-of-concept studies demonstrating the potential efficacy of targeting these lesions. Another increasingly recognised important contribution to pain in OA is sensitisation, which is associated with pain severity. Synovitis/effusion have been identified as potentially leading to development and worsening of sensitisation. Much work remains to be done in understanding the mechanisms by which structural pathology causes pain; such insights are urgently needed to develop new treatment approaches to help millions of people worldwide who are burdened by pain from OA.
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Treating chronic musculoskeletal pain, and chronic joint pain (osteoarthritis (OA)) in particular, is challenging as the peripheral and central pain mechanisms are not fully discovered, and safe and as efficient analgesic drugs are not available. In general, the preclinical models of OA are limited to provide fundamental understanding of the pain mechanisms involved in patients with chronic joint pain (1). The pain associated with joint discomfort is highly variable, often underestimated by clinicians, and shows only modest association with crude radiological scorings. One reason for the disconnect between the extent of structural damage and pain is neuroplastic changes occurring in the peripheral and central nervous system resulting in pain sensitisation impacting the patient's experience of pain. In recent years, a variety of human quantitative and mechanistic pain assessment tools (Quantitative Sensory Testing, QST) have been developed, providing new opportunities for diagnostic phenotyping of OA patients and the associated degree of sensitisation. Mechanistic phenotyping has revealed specific subgroups of specifically sensitised OA patients, and been used as a predictive guideline to evaluate which patients are most likely to experience continued chronic pain after an otherwise technically successful knee replacement (chronic postoperative pain). Furthermore, such techniques may be used to profile new or existing drugs together with other e.g. cognitive or behavioural therapies with the potential to manage joint pain.
Article
Background: Synovial hypertrophy, synovial effusions, and abnormalities in the subchondral bone play a key role in the pathogenesis of osteoarthritis (OA) and are associated with pain. Understanding and careful clinical assessment together with better imaging such as magnetic resonance imaging (MRI) of the knee may improve treatment strategies. The aim of this cross-sectional study was to investigate the associations between the structural findings on MRI (bone marrow lesions [BMLs], synovitis, cartilage defects, meniscal lesions), X-ray examination (Kellgren and Lawrence [K/L] grade), and psychological aspects with pain in patients with knee osteoarthritis (KOA). Methods: In this study, patients with symptomatic KOA were included. Knee radiographs were acquired and scored according to the K/L score. MRI was performed with a 1.5 T whole-body scanner; the presence of the following alterations was collected: BMLs, infrapatellar fat pad (IFP) synovitis, condral defects, and meniscal tears. Knee pain was assessed with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale. The Mental Component Summary Scale Score (MCS) of the Medical Outcomes Study Short-Form 36 Health Survey (SF-36) questionnaire was used to evaluate psychological impact. Results: BMLs were detected in 57 (38.3%) subjects of 149 participants (aged 51-81 years, female 75.8%). Cartilage defects were found in 91.9% of patients, IFP synovitis in 37.5%, meniscal lesions in 34.9%. In multiple regression analyses, WOMAC knee pain was significantly associated with the volume of the BMLs (p = 0.0001), IFP synovitis (p = 0.0036), and SF-36 MCS (p = 0.0001), but not with K/L grades, meniscal lesion score, cartilage defect, sex, age, educational level, disease duration and BMI. Conclusion: In symptomatic KOA patients, MRI features, such as larger BMLs, IFP synovitis, and high levels of psychological distress, are associated with greater knee pain. Confirmation of these findings in the prospective studies of KOA is needed.
Article
Intra-articular corticosteroid injections are a long-established treatment for knee osteoarthritis (OA), but new findings indicate they are not effective, and even potentially harmful. Is it time to rethink the use of this treatment?
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With recent technologic advances and availability of sophisticated computer software and analytical strategies, imaging plays an increasingly important role in understanding the disease process of osteoarthritis (OA). Radiography has limitations in that it can visualize only limited features of OA, such as osteophytes and joint space narrowing, but remains the most commonly used modality for establishing an imaging-based diagnosis of OA. This article describes the roles and limitations of different imaging modalities and discusses the optimum imaging protocol, imaging diagnostic criteria of OA, differential diagnoses, and what the referring physician needs to know.
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Importance Synovitis is common and is associated with progression of structural characteristics of knee osteoarthritis. Intra-articular corticosteroids could reduce cartilage damage associated with synovitis but might have adverse effects on cartilage and periarticular bone. Objective To determine the effects of intra-articular injection of 40 mg of triamcinolone acetonide every 3 months on progression of cartilage loss and knee pain. Design, Setting, and Participants Two-year, randomized, placebo-controlled, double-blind trial of intra-articular triamcinolone vs saline for symptomatic knee osteoarthritis with ultrasonic features of synovitis in 140 patients. Mixed-effects regression models with a random intercept were used to analyze the longitudinal repeated outcome measures. Patients fulfilling the American College of Rheumatology criteria for symptomatic knee osteoarthritis, Kellgren-Lawrence grades 2 or 3, were enrolled at Tufts Medical Center beginning February 11, 2013; all patients completed the study by January 1, 2015. Interventions Intra-articular triamcinolone (n = 70) or saline (n = 70) every 12 weeks for 2 years. Main Outcomes and Measures Annual knee magnetic resonance imaging for quantitative evaluation of cartilage volume (minimal clinically important difference not yet defined), and Western Ontario and McMaster Universities Osteoarthritis index collected every 3 months (Likert pain subscale range, 0 [no pain] to 20 [extreme pain]; minimal clinically important improvement, 3.94). Results Among 140 randomized patients (mean age, 58 [SD, 8] years, 75 women [54%]), 119 (85%) completed the study. Intra-articular triamcinolone resulted in significantly greater cartilage volume loss than did saline for a mean change in index compartment cartilage thickness of −0.21 mm vs −0.10 mm (between-group difference, −0.11 mm; 95% CI, −0.20 to −0.03 mm); and no significant difference in pain (−1.2 vs −1.9; between-group difference, −0.6; 95% CI, −1.6 to 0.3). The saline group had 3 treatment-related adverse events compared with 5 in the triamcinolone group and had a small increase in hemoglobin A1c levels (between-group difference, −0.2%; 95% CI, −0.5% to −0.007%). Conclusions and Relevance Among patients with symptomatic knee osteoarthritis, 2 years of intra-articular triamcinolone, compared with intra-articular saline, resulted in significantly greater cartilage volume loss and no significant difference in knee pain. These findings do not support this treatment for patients with symptomatic knee osteoarthritis. Trial Registration ClinicalTrials.gov Identifier: NCT01230424
Article
The increased information provided by modern imaging has led to its more extensive use. Our aim was to develop evidence-based recommendations for the use of imaging in the clinical management of the most common arthropathy, osteoarthritis (OA). A task force (including rheumatologists, radiologists, methodologists, primary care doctors and patients) from nine countries defined 10 questions on the role of imaging in OA to support a systematic literature review (SLR). Joints of interest were the knee, hip, hand and foot; imaging modalities included conventional radiography (CR), MRI, ultrasonography, CT and nuclear medicine. PubMed and EMBASE were searched. The evidence was presented to the task force who subsequently developed the recommendations. The strength of agreement for each recommendation was assessed. 17 011 references were identified from which 390 studies were included in the SLR. Seven recommendations were produced, covering the lack of need for diagnostic imaging in patients with typical symptoms; the role of imaging in differential diagnosis; the lack of benefit in monitoring when no therapeutic modification is related, though consideration is required when unexpected clinical deterioration occurs; CR as the first-choice imaging modality; consideration of how to correctly acquire images and the role of imaging in guiding local injections. Recommendations for future research were also developed based on gaps in evidence, such as the use of imaging in identifying therapeutic targets, and demonstrating the added value of imaging. These evidence-based recommendations and related research agenda provide the basis for sensible use of imaging in routine clinical assessment of people with OA.
Article
Objectives: To analyze if exercise interventions for patients with knee osteoarthritis (OA) following the American College of Sports Medicine (ACSM) definition of muscle strength training differs from other types of exercise, and to analyze associations between changes in muscle strength, pain, and disability. Methods: A systematic search in 5 electronic databases was performed to identify randomized controlled trials comparing exercise interventions with no intervention in knee OA, and reporting changes in muscle strength and in pain or disability assessed as standardized mean differences (SMD) with 95% confidence intervals (95% CI). Interventions were categorized as ACSM interventions or not-ACSM interventions and compared using stratified random effects meta-analysis models. Associations between knee extensor strength gain and changes in pain/disability were assessed using meta-regression analyses. Results: The 45 eligible trials with 4699 participants and 56 comparisons (22 ACSM interventions) were included in this analysis. A statistically significant difference favoring the ACSM interventions with respect to knee extensor strength was found [SMD difference: 0.448 (95% CI: 0.091-0.805)]. No differences were observed regarding effects on pain and disability. The meta-regressions indicated that increases in knee extensor strength of 30-40% would be necessary for a likely concomitant beneficial effect on pain and disability, respectively. Conclusion: Exercise interventions following the ACSM criteria for strength training provide superior outcomes in knee extensor strength but not in pain or disability. An increase of less than 30% in knee extensor strength is not likely to be clinically beneficial in terms of changes in pain and disability (PROSPERO: CRD42014015344).
Article
Objective: The aims of the present knee osteoarthritis (KOA)-study were to: i) describe and compare the changes in MRI-measures of synovitis following an exercise program preceded by an intra-articular injection of either corticosteroid or isotonic saline and ii) investigate if any of the changes in patient reported outcome measures (PROMs) were associated with changes in MRI-measures of synovitis. Design: We performed a randomized, double-blinded, placebo-controlled clinical trial evaluating the effects of intra-articular corticosteroid vs. placebo injections given before exercise therapy in KOA-patients. PROMs were assessed using the KOOS (knee injury and osteoarthritis outcome score). Synovitis was assessed on conventional non-contrast-enhanced, conventional contrast-enhanced and dynamic-contrast-enhanced MRI. PROMs and MRIs were obtained prior to the intra-articular injection, after termination of the exercise program (week 14-primary time point) and week 26. Results: Of 100 randomized participants (50 in each allocation group), 91 had complete MRI-data at baseline (63% female, mean age: 62 years, median Kellgren-Lawrence-grade: 3). There were no statistically significant differences between the two interventions in regards of changes in MRI-measures of synovitis at any time-point. At week 14, we found no statistical significant MRI-explanatory variables of either of the PROMs. Conclusions: The present study does not justify the use of intra-articular corticosteroids over intra-articular saline when combined with an exercise program for reduction of synovitis in KOA. The improvement in pain and function following the intervention with intra-articular corticosteroids/saline and exercise could not be explained by a decrease in synovitis on MRI indicating other pain causing/relieving mechanisms in KOA. Eudra-ct number: 2012-002607-18.
Article
Objectives: To investigate the association between MRI, macroscopic and histological assessments of synovitis in end-stage knee osteoarthritis (KOA). Methods: Synovitis of end-stage osteoarthritic knees was assessed using non-contrast-enhanced (CE), CE-MRI and dynamic-CE (DCE)-MRI prior to total knee replacement and correlated with microscopic and macroscopic assessments of synovitis obtained intraoperatively. Multiple bivariate correlations were used with a pre-specified threshold of 0.70 for significance. Also, multiple regression analyses with different subsets of MRI-variables as explanatory variables and the histology score as outcome variable were performed with the intention to find MRI-variables that best explain the variance in histological synovitis (i.e. highest R(2)). A stepped approach was taken starting with basic characteristics and non-CE MRI-variables (model 1), after which CE-MRI-variables were added (model 2) with the final model also including DCE-MRI-variables (model 3). Results: 39 patients (56.4% women, mean age 68 years, Kellgren-Lawrence grade 4) had complete MRI and histological data. Only the DCE-MRI variable MExNvoxel (surrogate of the volume and degree of synovitis) and the macroscopic score showed correlations above the pre-specified threshold for acceptance with histological inflammation. The maximum R(2)-value obtained in Model 1 was R(2)=0.39. In Model 2, where the CE-MRI-variables were added, the highest R(2)=0.52. In Model 3, a four-variable model consisting of the gender, one CE-MRI and two DCE-MR-variables yielded a R(2)=0.71. Conclusion: DCE-MRI is correlated with histological synovitis in end-stage KOA and the combination of CE and DCE-MRI may be a useful, non-invasive tool in characterising synovitis in KOA.
Article
Psychosocial factors may explain some of the variation in pain reporting among individuals with knee OA. This has important potential implications for management; indeed, several studies have demonstrated that interventions may reduce knee pain without apparent halting or reversing of structural damage. Such interventions have included the simple provision of support by monthly telephone calls, self-management programs, and cognitive-behavioral approaches designed to teach patients ways of coping with their pain. These programs are even more effective if the spouse is involved. It should be noted that there may be a large placebo effect in these interventions, and the degree to which patients are responding simply to an interest being taken in them and their problems is unclear; at least one study has shown that formal cognitive-behavioral therapy is no better than didactic education at improving pain and function in knee OA (though both are beneficial). Many studies examining the role of psychosocial factors have suffered from poor design; many, for example, fail to control for radiographic severity. Future studies should define how pain is identified (dichotomous, ever/never/current, severity), differentiate community and hospital subjects, and separate patients by type and location of OA. Studies should also control for other factors potentially associated with pain: obesity, comorbidity, muscle weakness, and aerobic fitness. Prospective studies would allow clarification of the cause and effect relationship between anxiety, depression, and pain, both in the community and in patients who have elected to seek medical help. In this way, we may increase our understanding of the complex interaction between mood, social factors, and pain reporting in knee OA and, thus, improve the effectiveness, already equivalent to many pharmacologic interventions, of treatments designed to address psychosocial factors.
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Metabolic Syndrome; Obesity; AMPK; Sirtuins; Adipokines; Energy metabolism
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Purpose: Exercise is effective for reducing knee osteoarthritis (OA) pain but effect sizes vary widely. Moreover, not all knee OA patients perceive beneficial effects. Tailoring specific exercises to subgroups of knee OA patients may increase effectivity. Bone marrow lesions (BMLs) have been suggested as a criterion to define such subgroups. This study aimed to investigate whether BMLs' presence/absence is related to treatment outcomes in a group of knee OA patients who exercised for 18 weeks. Methods: Subjects with symptomatic knee OA started a strength or walking exercise program. BMLs' presence at baseline was assessed. Pain was assessed before and after the intervention with the intermittent and constant osteoarthritis pain (ICOAP) questionnaire. Also the global perceived effect (GPE) on the patient's complaints was rated. Results: Thirty-five patients (strength (N = 17) and walking (N = 18)) were analyzed for BMLs. BMLs were present in 25 (71%) knees. Five (14%) patients dropped out and 19 (54%) improved (GPE ≥5). All dropouts had BMLs, but no difference was seen between dropouts and retainers (p > 0.05). Pain scores did not differ between intervention groups (p > 0.05) or between patients with BMLs and without BMLs (p > 0.05). Conclusions: Pain scores and GPE was not different between knee OA patients with and without baseline BMLs in this sample. Implications for Rehabilitation Both walking and strengthening exercises are effective means of improving pain in patients with knee osteoarthritis. In a relatively small sample, this study shows that the presence or absence of subchondral bone marrow lesions, as seen on magnetic resonance images, is not related to treatment outcomes.
Article
Over the past decades, the role of low-grade systemic inflammation has been acknowledged in several chronic musculoskeletal conditions.1 For many of these musculoskeletal conditions, exercise therapy is one of the most effective non-surgical and non-pharmacological treatments and the recommended treatment of first choice.1 ,2 Most guidelines do not provide specific guidance on the content of the exercise therapy, since different modalities of exercise therapy show comparable effectiveness. This highlights the lack of knowledge on the possible mechanisms of action of exercise therapy for musculoskeletal conditions and this black box phenomenon makes optimising the positive effects of physical exercise interventions difficult. We therefore possibly do not provide these patients an optimal treatment for their symptoms when prescribing a physical exercise intervention. The comparable effectiveness for different modalities of exercise therapy also suggests that systemic effects might be more important than local effects. One such systemic effect might be systemic inflammation. Individuals who are more physically active show lower …
Article
Objective: To estimate the lifetime risk of knee osteoarthritis (OA) and total knee replacement (TKR) in persons sustaining ACL tear by age 25. Methods: We used the Osteoarthritis Policy Model to project the cumulative incidence of symptomatic knee OA requiring TKR in persons with: 1) no prevalent or incident injury; 2) isolated ACL tear, surgically treated; 3) isolated ACL tear, non-operatively treated; or 4) prevalent history or surgically treated ACL and meniscal tear (MT). We estimated MT prevalence and incidence and increased risk of knee OA associated with ACL injury and MT from published literature. We conducted a range of sensitivity analyses to examine the impact of uncertainty in input parameters. Results: Estimated lifetime risk of symptomatic knee OA was 34% for the cohort with ACL injury and MT, compared to 14% for the no injury cohort. ACL injury without MT was associated with a lifetime risk of knee OA between 16%-17%, depending on ACL treatment modality. Estimated lifetime risk of TKR ranged from 6% in the no injury cohort to 22% for the ACL injury and MT cohort. Subjects in the ACL injury and MT cohort developed OA ∼1.5 years earlier (55.7 vs. 57.1) and underwent TKR ∼2 years earlier (66 vs. 68) than the cohort without knee injuries. Conclusions: Sustaining ACL injury early in adulthood leads to greater lifetime risk and earlier onset of knee OA and TKR; concomitant MTs compound this risk. These data provide insight into the impact of sustainable injury prevention interventions in young adults. This article is protected by copyright. All rights reserved.
Article
Objective: To conduct a systematic review and meta-analysis to synthesise evidence regarding measurement properties of the Knee injury and Osteoarthritis Outcome Score (KOOS). Design: A comprehensive literature search identified 37 eligible papers evaluating KOOS measurement properties in participants with knee injuries and/or osteoarthritis. Methodological quality was evaluated using the COSMIN checklist. Where possible, meta-analysis of extracted data was conducted for all studies and stratified by age and knee condition; otherwise narrative synthesis was performed. Results: KOOS has adequate internal consistency, test-retest reliability and construct validity in young and old adults with knee injuries and/or osteoarthritis. The ADL subscale has better content validity for older patients and Sport/Rec for younger patients with knee injuries, while the Pain subscale is more relevant for painful knee conditions. The five-factor structure of the original KOOS is unclear. There is some evidence that the KOOS subscales demonstrate sufficient unidimensionality, but this requires confirmation. Although measurement error requires further evaluation, the minimal detectable change for KOOS subscales ranges from 14.3 to 19.6 for younger individuals, and ≥20 for older individuals. Evidence of responsiveness comes from larger effect sizes following surgical (especially total knee replacement) than non-surgical interventions. Conclusions: KOOS demonstrates adequate content validity, internal consistency, test-retest reliability, construct validity and responsiveness for age- and condition-relevant subscales. Structural validity, cross-cultural validity and measurement error require further evaluation, as well as construct validity of KOOS-PS. Suggested order of subscales for different knee conditions can be applied in hierarchical testing of endpoints in clinical trials.
Article
Objectives: To investigate the association between pain and peripatellar-synovitis on static and dynamic contrast-enhanced MRI in knee osteoarthritis. Methods: In a cross-sectional setting, knee synovitis was assessed using 3-Tesla MRI and correlated with pain using the knee injury and osteoarthritis outcome score (KOOS). Synovitis was assessed in the peripatellar recesses with: (i) dynamic contrast-enhanced (DCE)-MRI, using both pharmacokinetic and heuristic models, (ii) contrast-enhanced (CE)-MRI, and (iii) non-CE-MRI. The DCE-MRI variable IRExNvoxel was chosen as the primary variable in the analyses. Results: Valid data were available in 94 persons with a mean age of 65 years, a BMI of 32.3kg/m(2) and a mean Kellgren-Lawrence grade of 2.5. IRExNvoxel showed a statically significant correlation with KOOS-Pain (r=-0.34; p=0.001), as was the case with all DCE-variables but one. Correlations between static MRI-variables and KOOS-Pain ranged between -0.21<r<-0.29 (p<0.040). Intraclass correlation coefficients ranged between 0.90-0.99 for the heuristic and 0.66-0.93 for the pharmacokinetic DCE-MRI variables. Conclusions: The results confirm an association between peripatellar-synovitis and pain in KOA. Overall, DCE-MRI showed stronger correlations with KOOS-Pain compared to static MRI. DCE-MRI analyses were highly reproducible and have the potential to be used to further investigate the role of inflammation and perfusion in KOA.
Article
Objectives: The aetiology of bone marrow lesions (BMLs) in knee osteoarthritis (OA) is poorly understood. We employed three-dimensional (3D) active appearance modelling (AAM) to study the spatial distribution of BMLs in an OA cohort and compare this with the distribution of denuded cartilage. Methods: Participants were selected from the Osteoarthritis Initiative progressor cohort with Kellgren-Lawrence scores ≥2, medial joint space narrowing and osteophytes. OA and ligamentous BMLs and articular cartilage were manually segmented. Bone surfaces were automatically segmented by AAM. Cartilage thickness of <0.5 mm was defined as denuded and ≥0.5-1.5 mm as severely damaged. Non-quantitative assessment and 3D population maps were used for analysing the comparative position of BMLs and damaged cartilage. Results: 88 participants were included, 45 men, mean age (SD) was 61.3 (9.9) years and mean body mass index was 31.1 (4.6) kg/m(2). 227 OA and 107 ligamentous BMLs were identified in 86.4% and 73.8% of participants; OA BMLs were larger. Denuded cartilage was predominantly confined to a central region on the medial femur and tibia, and the lateral facet of the trochlear femur. 67% of BMLs were colocated with denuded cartilage and a further 21% with severe cartilage damage. In the remaining 12%, 25/28 were associated with cartilage defects. 74% of all BMLs were directly opposing (kissing) another BML across the joint. Conclusions: There was an almost exclusive relationship between the location of OA BML and cartilage denudation, which itself had a clear spatial pattern. We propose that OA, ligamentous and traumatic BMLs represent a bone response to abnormal loading.
Article
This is the protocol for a review and there is no abstract. The objectives are as follows: The purpose of this review is to determine whether adjunctive therapy when used in addition to exercise therapy is beneficial for people with hip or knee osteoarthritis, compared with exercise only or exercise delivered in conjunction with a placebo adjunctive therapy.
Article
One of the most widespread words in medicine is the placebo and placebo effect, although it is not always clear what it means exactly. Recent progress in biomedical research has allowed a better clarification of the placebo effect. This is an active psychobiological phenomenon which takes place in the patient's brain and that is capable of influencing both the course of a disease and the response to a therapy. The psychosocial context around the patient is crucial to placebo effects, for example the doctor's words and attitudes, and this may have a profound impact on the patient's brain which, in turn, may affect several physiological functions of the body. This book emphasizes that there is not a single placebo effect but many. The book critically reviews them in different medical conditions, such as pain, neurological disorders, psychiatric and behavioural disorders, immune and endocrine systems, cardiovascular and respiratory systems, gastrointestinal and genitourinary disorders, as well as some special conditions, such as oncology, surgery, sports medicine, and acupuncture.
Article
The objective of this study was to examine the effect of high-intensity exercise on interleukin-15 (IL-15) expression in rabbit synovia. We utilized 24 New Zealand white rabbits, which were randomly divided equally into high-intensity exercise and control groups. The former were forced to run for 60 min/day over 4 weeks at the speed of 30 m/min. The histological changes of cartilage and knee joint synovia were investigated with hematoxylin and eosin staining. Immunohistochemistry and enzyme-linked immunosorbent assays were performed to measure IL-15 expression. From these analyses, we identified knee articular cartilage damage and synovitis in the high-intensity exercise group. This group also exhibited higher IL-15 expression in their synovial fluid and tissues than was observed in the control group (P < 0.05). These results suggested that high-intensity exercise might lead to synovitis and articular cartilage damage, and that IL-15 overexpression in synovia might be associated with post-traumatic osteoarthritis.
Article
Background: Knee osteoarthritis is a leading cause of chronic pain, disability, and decreased quality of life. Despite the long-standing use of intra-articular corticosteroids, there is an ongoing debate about their benefits and safety. This is an update of a Cochrane review first published in 2005. Objectives: To determine the benefits and harms of intra-articular corticosteroids compared with sham or no intervention in people with knee osteoarthritis in terms of pain, physical function, quality of life, and safety. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE (from inception to 3 February 2015), checked trial registers, conference proceedings, reference lists, and contacted authors. Selection criteria: We included randomised or quasi-randomised controlled trials that compared intra-articular corticosteroids with sham injection or no treatment in people with knee osteoarthritis. We applied no language restrictions. Data collection and analysis: We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain, function, quality of life, joint space narrowing, and risk ratios (RRs) for safety outcomes. We combined trials using an inverse-variance random-effects meta-analysis. Main results: We identified 27 trials (13 new studies) with 1767 participants in this update. We graded the quality of the evidence as 'low' for all outcomes because treatment effect estimates were inconsistent with great variation across trials, pooled estimates were imprecise and did not rule out relevant or irrelevant clinical effects, and because most trials had a high or unclear risk of bias. Intra-articular corticosteroids appeared to be more beneficial in pain reduction than control interventions (SMD -0.40, 95% CI -0.58 to -0.22), which corresponds to a difference in pain scores of 1.0 cm on a 10-cm visual analogue scale between corticosteroids and sham injection and translates into a number needed to treat for an additional beneficial outcome (NNTB) of 8 (95% CI 6 to 13). An I(2) statistic of 68% indicated considerable between-trial heterogeneity. A visual inspection of the funnel plot suggested some asymmetry (asymmetry coefficient -1.21, 95%CI -3.58 to 1.17). When stratifying results according to length of follow-up, benefits were moderate at 1 to 2 weeks after end of treatment (SMD -0.48, 95% CI -0.70 to -0.27), small to moderate at 4 to 6 weeks (SMD -0.41, 95% CI -0.61 to -0.21), small at 13 weeks (SMD -0.22, 95% CI -0.44 to 0.00), and no evidence of an effect at 26 weeks (SMD -0.07, 95% CI -0.25 to 0.11). An I(2) statistic of ≥ 63% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity≤0.001), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.43). There was evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.05) or at least 100 participants per group (P=0.013), in trials that used concomittant viscosupplementation (P=0.08), and in trials that used concomitant joint lavage (P≤0.001).Corticosteroids appeared to be more effective in function improvement than control interventions (SMD -0.33, 95% CI -0.56 to -0.09), which corresponds to a difference in functions scores of -0.7 units on standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10 and translates into a NNTB of 10 (95% CI 7 to 33). An I(2) statistic of 69% indicated a moderate to large degree of between-trial heterogeneity. A visual inspection of the funnel plot suggested asymmetry (asymmetry coefficient -4.07, 95% CI -8.08 to -0.05). When stratifying results according to length of follow-up, benefits were small to moderate at 1 to 2 weeks after end of treatment (SMD -0.43, 95% CI -0.72 to -0.14), small to moderate at 4 to 6 weeks (SMD -0.36, 95% CI -0.63 to -0.09), and no evidence of an effect at 13 weeks (SMD -0.13, 95% CI -0.37 to 0.10) or at 26 weeks (SMD 0.06, 95% CI -0.16 to 0.28). An I(2) statistic of ≥ 62% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity≤0.004), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.52). We found evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.023), in unpublished trials (P=0.023), in trials that used non-intervention controls (P=0.031), and in trials that used concomitant viscosupplementation (P=0.06).Participants on corticosteroids were 11% less likely to experience adverse events, but confidence intervals included the null effect (RR 0.89, 95% CI 0.64 to 1.23, I(2)=0%). Participants on corticosteroids were 67% less likely to withdraw because of adverse events, but confidence intervals were wide and included the null effect (RR 0.33, 95% CI 0.05 to 2.07, I(2)=0%). Participants on corticosteroids were 27% less likely to experience any serious adverse event, but confidence intervals were wide and included the null effect (RR 0.63, 95% CI 0.15 to 2.67, I(2)=0%).We found no evidence of an effect of corticosteroids on quality of life compared to control (SMD -0.01, 95% CI -0.30 to 0.28, I(2)=0%). There was also no evidence of an effect of corticosteroids on joint space narrowing compared to control interventions (SMD -0.02, 95% CI -0.49 to 0.46). Authors' conclusions: Whether there are clinically important benefits of intra-articular corticosteroids after one to six weeks remains unclear in view of the overall quality of the evidence, considerable heterogeneity between trials, and evidence of small-study effects. A single trial included in this review described adequate measures to minimise biases and did not find any benefit of intra-articular corticosteroids.In this update of the systematic review and meta-analysis, we found most of the identified trials that compared intra-articular corticosteroids with sham or non-intervention control small and hampered by low methodological quality. An analysis of multiple time points suggested that effects decrease over time, and our analysis provided no evidence that an effect remains six months after a corticosteroid injection.
Article
To systematically summarise the literature on 1) the course of pain in patients with knee OA; 2) prognostic factors that predict deterioration of pain; 3) the course of physical functioning; and 4) prognostic factors that predict deterioration of physical functioning in persons with knee OA. A search was conducted in PubMed, CINAHL, Embase, Psych-INFO, and SPORTDiscus up to January 2014. A meta-analysis and a qualitative data synthesis were performed. Of the 58 studies included, 39 were of high quality. High heterogeneity across studies (I(2) > 90%) and within study populations (reflected by large standard deviations of change scores) was found. Therefore, the course of pain and physical functioning was interpreted to be indistinct. We found strong evidence for a number of prognostic factors predicting deterioration in pain (e.g. higher knee pain at baseline, bilateral knee symptoms and depressive symptoms). We also found strong evidence for a number of prognostic factors predicting deterioration in physical functioning (e.g. worsening in radiographic osteoarthritis, worsening of knee pain, lower knee extension strength, lower walking speed and higher comorbidity count). Because of high heterogeneity across studies and within study populations, no conclusions can be drawn with regard to the course of pain and physical functioning. These findings support current research efforts to define subgroups or phenotypes within knee osteoarthritis populations. Strong evidence was found for knee characteristics, clinical factors, and psychosocial factors as prognostics of deterioration of pain and physical functioning. This article is protected by copyright. All rights reserved. © 2015, American College of Rheumatology.
Article
To investigate the association between muscle perfusion in the peri-articular knee muscles assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and symptoms in patients with knee osteoarthritis (KOA). In a cross-sectional setting, muscle perfusion was quantified by DCE-MRI in KOA. Regions of interest were drawn around the peri-articular muscles, summed and averaged into one single "Total Muscle Volume" volume of interest (VOI). Symptoms were assessed via the Knee injury and Osteoarthritis Outcome Score (KOOS) (0: worst; 100: best). DCE-MRI and clinical data were analyzed in 94 patients. The typical participant was a woman with a mean age of 65 years, and a body mass index of 32 kg/m(2). Reduced multiple regression models analyzing the association between KOOS and DCE-MRI perfusion variables of Total Muscle Volume showed a statistically significant association between Nvoxel% and KOOS pain (0.41 (SE 0.14); p=0.0048). Nvoxel% was defined as the proportion of highly perfused voxels; i.e. the voxels that show an early and rapid increase on the signal intensity versus time curves, reach a plateau state (plateau pattern) and then showing a relatively rapid decline (washout pattern) relative to the total number of voxels within the muscle VOI. More widespread perfusion in the peri-articular knee muscles was associated with less pain in patients with KOA. These results give rise to investigations of the effects of exercise on muscle perfusion and its possible mediating role in the causal pathway between exercise and pain improvements in the conservative management of KOA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Article
Significant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Article
The objective was to develop a set of "best practices" for use as a primer for those interested in entering the clinical trials field for lifestyle diet and/or exercise interventions in osteoarthritis (OA), and as a set of recommendations for experienced clinical trials investigators. A subcommittee of the non-pharmacologic therapies committee of the OARSI Clinical Trials Working Group was selected by the Steering Committee to develop a set of recommended principles for non-pharmacologic diet/exercise OA randomized clinical trials. Topics were identified for inclusion by co-authors and reviewed by the subcommittee. Resources included authors' expert opinions, traditional search methods including MEDLINE (via PubMed), and previously published guidelines. Suggested steps and considerations for study methods (e.g., recruitment and enrollment of participants, study design, intervention and assessment methods) were recommended. The recommendations set forth in this paper provide a guide from which a research group can design a lifestyle diet/exercise randomized clinical trial in patients with OA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Article
The goal of this document is to update the original OARSI recommendations specifically for the design, conduct, and reporting of clinical trials that target symptom or structure modification among individuals with knee osteoarthritis (OA). To develop recommendations for the design, conduct, and reporting of clinical trials for knee OA we initially drafted recommendations through an iterative process. Members of the working group included representatives from industry and academia. After the working group members reviewed a final draft, they scored the appropriateness for recommendations. After the members voted we calculated the median score among the nine members of the working group who completed the score. The document includes 25 recommendations regarding randomization, blocking and stratification, blinding, enhancing accuracy of patient-reported outcomes (PRO), selecting a study population and index knee, describing interventions, patient-reported and physical performance measures, structural outcome measures, biochemical biomarkers, and reporting recommendations. In summary, the working group identified 25 recommendations that represent the current best practices regarding clinical trials that target symptom or structure modification among individuals with knee OA. These updated recommendations incorporate novel technologies (e.g., magnetic resonance imaging (MRI)) and strategies to address the heterogeneity of knee OA. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Article
Although physical exercise is the commonly recommended for osteoarthritis (OA) patients, the working mechanism behind the positive effects of physical exercise on pain and function is a black box phenomenon. In the present study we aimed to identify possible mediators in the relation between physical exercise and improvements of pain and function in OA patients. A systematic search for all studies evaluating the effects of physical exercise in OA patients and select those that additionally reported the change in any physiological factor from pre-to post-exercise. In total, 94 studies evaluating 112 intervention groups were included. Most included studies evaluated subjects with solely knee OA (96 out of 112 groups). Based on the measured physiological factors within the included studies, 12 categories of possible mediators were formed. Muscle strength and ROM/flexibility were the most measured categories of possible mediators with 61 and 21 intervention groups measuring one or more physiological factors within these categories, respectively. 60% (31 out of 52) of the studies showed a significant increase in knee extensor muscle strength and 71% (22 out of 31) in knee flexor muscle strength over the intervention period. All 5 studies evaluating extension impairments and 10 out of 12 studies (83%) measuring proprioception found a significant change from pre-to post-intervention. An increase of upper leg strength, a decrease of extension impairments and improvement in proprioception were identified as possible mediators in the positive association between physical exercise and OA symptoms. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.