Exercise and education vs intra-articular saline for knee osteoarthritis: a 1-year follow-up of a randomized trial.

OBJECTIVE: To assess the longer-term effect of the Good Life with osteoarthritis in Denmark (GLAD) exercise and education program relative to open-label placebo (OLP) on changes from baseline in core outcomes in individuals with knee osteoarthritis (OA). METHODS: In this 1-year follow-up of an open-label, randomized trial, patients with symptomatic and radiographically confirmed knee OA were monitored after being randomized to either the 8-week GLAD program or OLP given as 4 intra-articular saline injections over 8 weeks. The primary outcome was the change from baseline in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale after 1 year in the intention-to-treat population. Key secondary outcomes were the KOOS function and quality of life subscales, and Patients' Global Assessment of disease impact. RESULTS: 206 adults were randomly assigned: 102 to GLAD and 104 to OLP, of which only 137 (63/74 GLAD/OLP) provided data at 1 year. At one year the mean changes in KOOS pain were 8.4 for GLAD and 7.0 for OLP (Difference: 1.5 points; 95% CI -2.6 to 5.5). There were no between-group differences in any of the secondary outcomes. CONCLUSIONS: In this 1-year follow-up of individuals with knee OA, the 8-week GLAD program and OLP both provided minor longer-term benefits with no group difference. These results require confirmation given the significant loss to follow-up. TRIAL REGISTRATION NUMBER: NCT03843931.

Who are likely to benefit from the Good Life with osteoArthritis in Denmark (GLAD) exercise and education program? An effect modifier analysis of a randomised controlled trial.

OBJECTIVE: To identify contextual factors that modify the treatment effect of the 'Good Life with osteoArthritis in Denmark' (GLAD) exercise and education programme compared to open-label placebo (OLP) on knee pain in individuals with knee osteoarthritis (OA). METHODS: Secondary effect modifier analysis of a randomised controlled trial. 206 participants with symptomatic and radiographic knee OA were randomised to either the 8-week GLAD programme (n = 102) or OLP given as 4 intra-articular saline injections over 8 weeks (n = 104). The primary outcome was change from baseline to week 9 in the Knee injury and Osteoarthritis Outcome Score questionnaire (KOOS) pain subscale (range 0 (worst) to 100 (best)). Subgroups were created based on baseline information: BMI, swollen study knee, bilateral radiographic knee OA, sports participation as a young adult, sex, median age, a priori treatment preference, regular use of analgesics (NSAIDs or paracetamol), radiographic disease severity, and presence of constant or intermittent pain. RESULTS: Participants who reported use of analgesics at baseline seem to benefit from the GLAD programme over OLP (subgroup contrast: 10.3 KOOS pain points (95% CI 3.0 to 17.6)). Participants with constant pain at baseline also seem to benefit from GLAD over OLP (subgroup contrast: 10.0 points (95% CI 2.8 to 17.2)). CONCLUSIONS: These results imply that patients who take analgesics or report constant knee pain, GLAD seems to yield clinically relevant benefits on knee pain when compared to OLP. The results support a stratified recommendation of GLAD as management of knee OA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03843931. EudraCT number 2019-000809-71.

The effect of intra-articular glucocorticosteroids and exercise on symptoms and bone marrow lesions in knee osteoarthritis: a secondary analysis of results from a randomized controlled trial.

OBJECTIVE: To evaluate if the relative volume of bone marrow lesions (BMLs) changed in patients with knee osteoarthritis (OA) during a therapeutic study. DESIGN: This study is a sub-study to a larger clinical trial which compared the clinical effects of intra-articular corticosteroid injection in knee OA to placebo injection, both given prior to exercise therapy. Clinical assessment using the Knee injury and Osteoarthritis Outcome Score (KOOS) and magnetic resonance imaging (MRI) examinations with BML assessments were performed at baseline and follow-up after 14 weeks and 26 weeks, respectively. The BML volume was determined using a computer assisted method focusing on participants with valid baseline and follow-up MRI examinations. Any changes in BML and KOOS were analyzed and investigated for associations. RESULTS: Fifty participants received steroid and placebo injection, respectively, of which 41 and 45 had complete MRI examinations at week 14, and 36 and 33 at week 26, respectively. All participants received 12 weeks of exercise. A significant change in relative BML volume was observed between the corticosteroid group and the placebo group after 14 weeks [-1.1% vs 2.7%; between-group difference, 3.8% (95% CI 0.5-7.0)] but not after 26 weeks [0.8% vs 1.6%; between-group difference, 0.8% (95% CI -2.8 to 4.4)]. No significant association was found between changes in relative BML volume and KOOS. CONCLUSIONS: Despite the statistically significant difference in BML volume at 14 weeks after corticosteroid injection and 12 weeks exercise therapy compared to placebo injection and exercise, there is very little evidence on a relationship between corticosteroids and BML volume. EU CLINICAL TRIALS REGISTER: EudraCT number: 2012-002607-18.

Osteoarthritis year in review 2016: imaging.

PURPOSE: The current narrative review covers original research related to imaging in osteoarthritis (OA) in humans published in English between April 1st 2015 and March 31st 2016, in peer reviewed journals available in Medline via PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). METHODS: Relevant studies in humans, subjectively decided by the authors, contributing significantly to the OA imaging field, were selected from an extensive Medline search using the terms "Osteoarthritis" in combination with "MRI", "Imaging", "Radiography", "X-rays", "Ultrasound", "Computed tomography", "Nuclear medicine", "PET-CT", "PET-MRI", "Scintigraphy", "SPECT". Publications were sorted according to relevance for the OA imaging research community with an emphasis on high impact special interest journals using the software for systematic reviews www.covidence.org. RESULTS: An overview of newly published studies compared to studies reported previous years is presented, followed by a review of selected imaging studies of primarily knee, hip and hand OA focussing on (1) results for detection of OA and OA-related pathology (2) studies dealing with treatments and (3) studies focussing on prognosis of disease progression or joint replacement. A record high number of 1420 articles were published, among others, of new technologies and tools for improved morphological and pathophysiological understanding of OA-related changes in joints. Also, imaging data were presented of monitoring treatment effect and prognosis of OA progression, primarily using established radiographic, magnetic resonance imaging (MRI), and ultrasound (US) methods. CONCLUSION: Imaging continues to play an important role in OA research, where several exciting new technologies and computer aided analysis methods are emerging to complement the conventional imaging approaches.

The effects of intra-articular glucocorticoids and exercise on pain and synovitis assessed on static and dynamic magnetic resonance imaging in knee osteoarthritis: exploratory outcomes from a randomized controlled trial.

OBJECTIVE: The aims of the present knee osteoarthritis (KOA)-study were to: (1) describe and compare the changes in magnetic resonance imaging (MRI)-measures of synovitis following an exercise program preceded by an intra-articular injection of either corticosteroid or isotonic saline and (2) 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 (CE) and dynamic contrast-enhanced (DCE) 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.

Non-nociceptive pain in rheumatoid arthritis is frequent and affects disease activity estimation: cross-sectional data from the FRAME study.

BACKGROUND: The painDETECT questionnaire (PDQ) is a mechanism-based pain classification tool assigning patients to one of three categories depending on the quality of the experienced pain. Patients with non-nociceptive pain score high on the PDQ. The objective was to assess the proportions of the three PDQ classification groups in patients with rheumatoid arthritis (RA) and to explore differences in clinical characteristics. METHOD: RA patients initiating or escalating their RA therapy were included prospectively and underwent a thorough examination programme. Low (PDQ score < 13), medium (PDQ score 13-18), and high (PDQ score > 18) scores indicate nociceptive, unclear/possible neuropathic, or neuropathic pain mechanisms, respectively. RESULTS: The 102 included patients were classified into the following PDQ classification groups: low = 65%, medium = 23%, and high = 12%. Patients in the medium and high PDQ groups scored worse on indicators of anxiety, depression, disability, mental health-related quality of life, pain, and fatigue. They also had more tender points and an RA disease activity score based on 28 joints (DAS28) where a higher fraction of the composite score pertained to non-inflammatory factors compared to patients in the low PDQ classification group. There were no differences in objective inflammatory indices across groups. Multiple regression analysis demonstrated that the tender joint count (TJC) and the 36-item Short Form Health Survey (SF36) mental component summary (MCS) score were independently associated with the PDQ score. CONCLUSIONS: In patients initiating or intensifying medical treatment for their RA, non-nociceptive pain (PDQ score ≥ 13) is common. In these patients, the pain mechanisms result in increased disease activity scores on a non-inflammatory basis.

Changes in ultrasound assessed markers of inflammation following intra-articular steroid injection combined with exercise in knee osteoarthritis: exploratory outcome from a randomized trial.

OBJECTIVE: Knee osteoarthritis (KOA) is a multifactorial joint disease affecting many people worldwide. Recommended treatments for KOA include exercise and steroid injections, or a combination of these. The objective of this exploratory outcome analysis of a randomized trial was to assess changes in inflammation markers assessed by ultrasound imaging (US) in KOA secondary to intra-articular corticosteroid injection given prior to exercise therapy. DESIGN: This study is a sub-study to a larger clinical trial which compared the clinical effects of steroid injection in KOA to placebo injection, both given prior to exercise therapy. The US outcomes were changes from baseline in US-assessed synovial size, Doppler activity presence in the synovial membrane, and numbers of US-detected Baker's cysts. US was performed at baseline, week 14 (exercise stop), and week 26 (follow-up). RESULTS: Fifty participants received steroid injection, and 50 received placebo injection. All participants received 12 weeks of exercise. Forty-five and 44, respectively, completed the study. At week 14, the group difference in the change in synovium thickness was 2.2 mm (95%, confidence interval (CI) -0.5 to 4.8), P = 0.11. There were no group differences in the changes in distribution of patients with presence of synovial Doppler activity (P = 0.98) or Baker's cysts (P = 0.35). There were no statistically significant differences between groups at week 26 in any outcome. CONCLUSION: Intra-articular steroid injection of KOA-patients prior to a 3 months exercise programme did not reduce synovial hypertrophy, synovial Doppler activity, or Baker's cyst presence more than a placebo saline injection according to US-assessments. TRIAL REGISTRATION: EudraCT: 2012-002607-18.

Validity and reliability of 3D US for the detection of erosions in patients with rheumatoid arthritis using MRI as the gold standard.

PURPOSE: To test the reliability and validity of a 3D US erosion score in RA using MRI as the gold standard. MATERIALS AND METHODS: RA patients were examined with 3D US and 3 T MRI over the 2nd and 3rd metacarpophalangeal joints. 3D blocks were evaluated by two investigators. The erosions were estimated according to a semi-quantitative score (SQS) (0 - 3) and a quantitative score (QS) (mm²). MRI was evaluated according to the RAMRIS score. For the estimation of reliability, intra-class correlation coefficients (ICC) were used. Validity was tested using Spearman's rho (rs). The sensitivity and specificity were also calculated. RESULTS: 28 patients with RA were included. The ICC for the inter-observer reliability in the QS was 0.41 and 0.13 for the metacarpal bone and phalangeal bone, respectively, and 0.86 and 0.16, respectively, in the SQS.  The ICC for the intra-observer reliability in the QS was 0.75 and 0.48 for the metacarpal bone and phalangeal bone, respectively, and 0.83 and 0.60, respectively, in the SQS.  The correlation with MRI for the metacarpal bone was significant, with values of 0.73 (p = 0.0001) (SQ) and 0.74 (p = 0.0001) (SQS). For the phalangeal bone, bad correlation was found: 0.28 (p = 0.145) (SQ) and 0.26 (p = 0.57) (SQS). The sensitivity and specificity for the metacarpal bone were 86 % and 85 % respectively. For the phalangeal bone they were 60 % and 97 %, respectively. CONCLUSION: Good inter- and intra-observer reliability and correlation with MRI were seen in the assessment of erosions with 3D US in the metacarpal bone, while the results were low and insignificant for the phalangeal bone, indicating that 3D US still has room for improvement.

Ultrasound Doppler score correlates with OMERACT RAMRIS bone marrow oedema and synovitis score in the wrist joint of patients with rheumatoid arthritis.

PURPOSE: MRI is considered the standard of reference for advanced imaging in rheumatoid arthritis (RA). However, in daily clinical practice ultrasound (US) imaging with Doppler information is more versatile and often used for fast and dynamic assessment of joint inflammation. The aim was to compare low-field MRI scores with the US Doppler measurements in the wrist joint of patients with RA. MATERIAL AND METHODS: Fifty consecutive patients with RA (46 women & 4 men) completed both low-field dedicated extremity MRI (E-scan®, Esaote) and a high-end US (Sequioa®, Siemens) imaging of the wrist before initiating either biological treatment (n = 26) or intraarticular injection of Depomedrole® (n = 24). Mean age was 56 years (range 21 - 83 years); mean disease duration 87.2 months (range 4 - 349 months), mean DAS 28 4,8 (range 2 - 7). MRI was scored according to the OMERACT RAMRIS recommendations and US Doppler colour-fractions were determined. RESULTS: Using Spearman's rho, we found a relatively good to moderate correlation between the US colour-fraction and the total OMERACT bone marrow oedema and synovitis scores on MRI (r = 0.6; p < 0.001 and r = 0.4; p < 0.006 respectively). There was a trend but no significant correlation with the total OMERACT erosion score (r = 0.3; p = 0.06). CONCLUSION: Within limits, the OMERACT RAMRIS scores of inflammation in RA patients (bone marrow oedema and synovial enhancement) are comparable to the US colour-fraction measurements using a high-end US scanner. Both imaging modalities detect inflammation although showing different aspects of the inflammatory process in the wrist joint. The higher correlation between US colour-fractions and MRI bone marrow oedema indicates a potential importance of US Doppler in monitoring inflammatory disease changes in RA.

Comparison of two co-registration methods for real-time ultrasonography fused with MRI: a phantom study.

PURPOSE: To test the accuracy of spatial registration of real-time ultrasonography (US) fused with MRI in a phantom. MATERIALS AND METHODS: An US prototype system (LOGIQ, GE Healthcare) with incorporated software for fusion imaging was used to test two methods of co-registration in a phantom: co-registration from specific points, where common reference points identifiable on both MRI and US images were marked, and plane registration, where common planes identifiable on both MRI and US images were marked. In two series we performed co-registration from points and in one series we performed co-registration from planes. The accuracy of the co-registration was measured at 3 measuring points, defined before initiation of the study, and it was calculated as the root mean square deviation (RMSD), which corresponds to the standard deviation. It was measured in millimeters. Two observers each performed 30 co-registrations for each series, totaling 180 co-registrations. The difference between the methods and the observers was calculated using analysis of variance (two-way ANOVA). RESULTS: Co-registration was significantly more accurate when using the measuring points as co-registration points than when using points covering a different area of the phantom (p < 0.0001). The mean calculated RMSD when using the measuring points as co-registration points was 1.3 mm (95 % CI: 1.1 - 1.5 mm), when using points away from the measuring points: 4.0 mm (95 % CI: 3.2 - 4.8 mm), and when using planes for the co-registration: 3.8 mm (95 % CI: 3.2 - 4.4 mm). CONCLUSION: Image fusion involving real-time US has high accuracy and is easy to use in a phantom. Working within the area given by the co-registration points optimizes the accuracy. Image fusion is a promising tool for clinical US, since it provides the potential of benefiting from different imaging modalities in one examination.

Ultrasound colour Doppler measurements in a single joint as measure of disease activity in patients with rheumatoid arthritis--assessment of concurrent validity.

OBJECTIVE: Colour Doppler ultrasound (CDU) displays blood flow in the tissues and is able to detect hyperaemia. Because hyperaemia is part of the inflammatory response, the amount of CDU activity in the inflamed synovium may be used to quantify the inflammatory activity in RA. It has never been investigated if the amount of CDU activity in a single joint can be used to quantify disease activity in RA. METHODS: A total of 109 patients with RA and affection of the wrist joint underwent a standardized CDU examination assessing three positions in their most affected wrist at start up in biological treatment. On the same day the following measures of disease activity were collected: assessment of the number of tender and swollen joints, CRP, ESR and 28-joint disease activity score (DAS28). The amount of CDU activity was quantified by measuring the percentage of colour in the synovium--the colour fraction (CF). Correlation between CF and other measures of disease activity was calculated. RESULTS: There was a significant correlation between CF and DAS28 (r = 0.29; P < 0.001), swollen joint count (r = 0.35; P < 0.001), CRP (r = 0.5; P < 0.001) and ESR (r = 0.5; P < 0.001). No other significant correlations were found. CONCLUSION: A standardized ultrasound examination of a single affected wrist joint in patients with RA may be used as a measure of disease activity. More studies are needed to identify the number of joints needed to examine by CDU to obtain the best validity of Doppler measurements.

Quantification of colour Doppler activity in the wrist in patients with rheumatoid arthritis--the reliability of different methods for image selection and evaluation.

PURPOSE: The amount of colour Doppler activity in the inflamed synovium is used to quantify inflammatory activity. The measurements may vary due to image selection, quantification method, and point in cardiac cycle. This study investigated the test-retest reliability of ultrasound colour Doppler measurements in the wrist of patients with rheumatoid arthritis (RA) using different selection and quantification methods. MATERIALS AND METHODS: 14 patients with RA had their wrist scanned twice by the same investigator with an interval of 30 minutes. The images for analysis were selected either by the anatomical position only or by the anatomical position with maximum colour Doppler activity. Subsequently, the amount of colour Doppler was measured in an area defined by either the synovial tissue or by specific anatomical structures surrounding the synovial tissue. RESULTS: The best test-retest reliability was obtained when the images were selected guided by colour Doppler and the subsequent quantification was done in an area defined by anatomical structures. With this method, the intra-class coefficient ICC (2.1) was 0.95 and the within-subject SD (SW) was 0.017, indicating good reliability. In contrast, poor test-retest reliability was found if the images were selected by anatomical position only and the quantification was done in an area defined by the synovial tissue (ICC [2.1] = 0.48 and SW = 0.049). CONCLUSION: The study showed that colour Doppler measurements are reliable if the images for analysis are selected by anatomical position in combination with colour Doppler activity and the subsequent analysis is performed in an area defined by anatomical structures.

Ultrasound in finger joints: findings in normal subjects and pitfalls in the diagnosis of synovial disease.

PURPOSE: Grey-scale ultrasound may be used to visualise the amount of synovial tissue in patients with rheumatoid arthritis (RA). Different scoring systems have been developed. None of the scoring systems have been tested on a larger group of healthy joints, and it is therefore unknown to what extent synovial tissue is seen on grey-scale ultrasound in healthy joints. The objective of this study was to test two scoring systems on healthy volunteers. MATERIALS AND METHODS: 24 healthy men and women between 30 and 54 years underwent scanning of the MCP, PIP and DIP joints of their dominant hand. Each person was scanned in 69 positions. The images were graded on a scale from 0 to 4 with two scoring systems (I and II). Scores 0 - 1 were defined as normal and 2 - 4 as pathological. With scoring system I, only markedly hypoechoic synovium was graded. With scoring system II, marked hypoechogenicity was not a criterion. RESULTS: With system I, 89 % of the joints obtained at least one pathological score. With system II, 95 % of the joints obtained at least one pathological score. With both systems, women obtained higher scores than men, and the number of high scores increased with increasing age. CONCLUSION: An unacceptably high number of joints obtained pathological scores with both scoring systems in healthy volunteers. This indicates that many of the scores interpreted as pathological in patients with RA may just be normal findings, with increasing numbers in older patients.

Indications of inflammation visualized by ultrasound in osteoarthritis of the knee.

PURPOSE: Ultrasound examination of a group of patients with osteoarthritis (OA) of the knee for signs of inflammation. MATERIAL AND METHODS: 71 knees in 71 patients with osteoarthritis of the knee were examined with high-resolution gray-scale ultrasound combined with color and spectral Doppler. The medial, lateral, and antero-superior compartments were examined. Hyperemia was identified as presence of color Doppler signals in the synovial membrane. Low resistance flow was defined as a resistive index < 0.80 on spectral Doppler. RESULTS: Synovial thickening was found in all knees; fluid in 61 patients; and hyperemia (color Doppler activity) in 51 patients. Of these, 44 had arterial flow on spectral Doppler - 36 with a low resistance flow. When present, fluid and color Doppler activity was found in all three compartments, but with uneven distribution. CONCLUSION: The finding in the majority of cases of both effusions on B-mode US and Doppler activity confirms that there is a varying degree of inflammation in knee OA as diagnosed by the ACR criteria.