Accuracy of synovial fluid analysis compared to histology for the identification of calcium pyrophosphate crystals: an ancillary study of the OMERACT US Working Group - CPPD subgroup.

The aim of this study was to evaluate the accuracy of synovial fluid analysis in the identification of calcium pyrophosphate dihydrate crystals compared to microscopic analysis of joint tissues as the reference standard. This is an ancillary study of an international, multicentre cross-sectional study performed by the calcium pyrophosphate deposition disease (CPPD) subgroup of the OMERACT Ultrasound working group. Consecutive patients with knee osteoarthritis (OA) waiting for total knee replacement surgery were enrolled in the study from 2 participating centres in Mexico and Romania. During the surgical procedures, synovial fluid, menisci and hyaline cartilage were collected and analysed within 48 hours from surgery under transmitted light microscopy and compensated polarised light microscopy for the presence/absence of calcium pyrophosphate crystals. All slides were analysed by expert examiners on site, blinded to other findings. A dichotomic score (absence/ presence) was used for scoring both synovial fluid and tissues. Microscopic analysis of knee tissues was considered the gold standard. Sensitivity, specificity, accuracy, positive and negative predictive values of synovial fluid analysis in the identification of calcium pyrophosphate crystals were calculated. 15 patients (53% female, mean age 68 yo ± 8.4) with OA of grade 3 or 4 according to Kellgren-Lawrence scoring were enrolled. 12 patients (80%) were positive for calcium pyrophosphate crystals at the synovial fluid analysis and 14 (93%) at the tissue microscopic analysis. The overall diagnostic accuracy of synovial fluid analysis compared with histology for CPPD was 87%, with a sensitivity of 86% and a specificity of 100%, the positive predictive value was 100% and the negative predictive value was 33%. In conclusion synovial fluid analysis proved to be an accurate test for the identification of calcium pyrophosphate dihydrate crystals in patients with advanced OA.

Structural damage in rheumatoid arthritis assessed by musculoskeletal ultrasound: A systematic literature review by the Structural Joint Damage Task Force of the OMERACT Ultrasound Working Group.

OBJECTIVES: To identify and synthesize the evidence for the use and measurement properties of musculoskeletal ultrasound in assessing structural joint damage in patients with rheumatoid arthritis (RA). METHODS: A systematic literature search (SLR) of the PubMed, Embase and Cochrane Library was performed. Original articles were included published in English reporting on ultrasound of bone erosion, cartilage damage and the measurement properties of ultrasound according to the OMERACT filter 2.1. RESULTS: Of the 1.495 identified articles 149 were included in the final review, most of which reported on cross-sectional studies and used the OMERACT definitions for ultrasonographic pathology. Among these, bone erosions were assessed in 139 (93.3%), cartilage damage in 24 (16.1%), enthesophytes in 8 (5.4%), osteophytes in 15 (10.1%) and malalignment and ankylosis in a single (0.9%) study, respectively. Most studies (126/149, 84.6%) assessed the joints of the hands. The overwhelming majority of studies (127/149, 85.2%) assessed structural joint damage bilaterally. Validity, reliability and responsiveness were assessed in 21 (14.1%), 34 (22.8%) and 17 (11.4%) studies, respectively. CONCLUSION: While the results of this SLR suggest that ultrasound is a sensitive, reliable and feasible tool to detect damage in RA, they also highlight the need for further research and validation. Findings of this SLR will inform the next steps of the OMERACT Ultrasound Working Group in developing an ultrasound score for assessing structural joint damage in patients with RA.

Amendment of the OMERACT ultrasound definitions of joints' features in healthy children when using the DOPPLER technique.

BACKGROUND: Recently preliminary ultrasonography (US) definitions, in B mode, for normal components of pediatric joints have been developed by the OMERACT US group. The aim of the current study was to include Doppler findings in the evaluation and definition of normal joint features that can be visualized in healthy children at different age groups. METHODS: A multistep approach was used. Firstly, new additional definitions of joint components were proposed during an expert meeting. In the second step, these definitions, along with the preliminary B-mode-US definitions, were tested for feasibility in an exercise in healthy children at different age groups. In the last step, a larger panel of US experts were invited to join a web-based consensus process in order to approve the developed definitions using the Delphi methodology. A Likert scale of 1-5 was used to assess agreement. RESULTS: Physiological vascularity and fat pad tissue were identified and tested as two additional joint components in healthy children. Since physiological vascularity changes over the time in the growing skeleton, the final definition of Doppler findings comprised separate statements instead of a single full definition. A total of seven statements was developed and included in a written Delphi questionnaire to define and validate the new components. The final definitions for fat pad and physiological vascularity agreed by the group of experts reached 92.9% and 100% agreement respectively in a web survey. CONCLUSION: The inclusion of these two additional joints components which are linked to detection of Doppler signal in pediatric healthy joints will improve the identification of abnormalities in children with joint pathologies.

Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis.

BACKGROUND: In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA. METHODS: Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX. RESULTS: From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response. CONCLUSION: Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.

Is it time to revisit the role of ultrasound in rheumatoid arthritis management?

For over a decade, a large number of studies have highlighted the benefits of ultrasound (US) in the diagnosis and management of rheumatic diseases, especially rheumatoid arthritis (RA). However, its benefits in routine practice have been less studied and trials examining US as part of various clinical strategies are just emerging, with recent randomised trials examining the added value of US in tight-control paradigms. The conclusions of these trials have raised questions on the role of US in RA management. This Viewpoint analyses the recent studies, and discusses potential limitations in study designs as well as the methodological challenges of assessing the added value of an imaging technique.

Global ultrasound assessment of structural lesions in osteoarthritis: a reliability study by the OMERACT ultrasonography group on scoring cartilage and osteophytes in finger joints.

OBJECTIVE: Ultrasonography is sensitive for the evaluation of cartilage pathology and degree of osteophytes in patients with hand osteoarthritis (OA). High consistency of assessments is essential, and the OMERACT (Outcome Measures in Rheumatology) ultrasonography group took the initiative to explore the reliability of a global ultrasonography score in patients with hand OA using semiquantitative ultrasonography score of cartilage and osteophytes in finger joints. METHODS: Ten patients with hand OA were examined by 10 experienced sonographers over the course of two days. Semiquantitative scoring (0-3) was performed on osteophytes (carpo-metacarpal 1, metacarpo-phalangeal (MCP) 1-5, proximal interphalangeal 1-5 and distal interphalangeal 2-5 joints bilaterally with an ultrasonography atlas as reference) and cartilage pathology (MCP 2-5 bilaterally). A web-based exercise on static cartilage images was performed a month later. Reliability was assessed by use of weighted κ analyses. RESULTS: Osteophyte scores were evenly distributed, and the intraobserver and interobserver reliabilities were substantial to excellent (κ range 0.68-0.89 and mean κ 0.65 (day 1) and 0.67 (day 2), respectively). Cartilage scores were unevenly distributed, and the intraobserver and interobserver reliability was fair to moderate (κ range 0.46-0.66 and mean κ 0.39 (day 1) and 0.33 (day 2), respectively). The web-based exercise showed acceptable agreement for cartilage being normal (κ 0.47) or with complete loss (κ 0.68), but poor for the intermediate scores (κ 0.22-0.30). CONCLUSIONS: Use of the present semiquantitative ultrasonography scoring system for cartilage pathology in hand OA is not recommended (while normal or total loss of cartilage may be assessed). However, the OMERACT ultrasonography group will endorse the use of semiquantitative scoring of osteophytes with the ultrasonography atlas as reference.

Educational recommendations for the conduct, content and format of EULAR musculoskeletal ultrasound Teaching the Teachers Courses.

OBJECTIVE: To produce educational guidelines for the conduct, content and format of theoretical and practical teaching at EULAR musculoskeletal ultrasound (MSUS) Teaching the Teachers (TTT) Courses. METHODS: A Delphi-based procedure with 24 recommendations covering five main areas (Duration and place of the course; Faculty members; Content of the course; Evaluation of the teaching skills; TTT competency assessment) was distributed among a group of experts involved in MSUS teaching, in addition to an advisory educational expert being present. Consensus for each recommendation was considered achieved when the percentage of agreement was >75%. RESULTS: 21 of 24 invited participants responded to the first Delphi questionnaire (88% response rate). All 21 participants also responded to the second round. Agreement on 19 statements was obtained after two rounds. CONCLUSIONS: This project has led to the development of guidelines for the conduct, content and format of teaching at the EULAR MSUS TTT Courses that are organised annually, with the aim of training future teachers of EULAR MSUS Courses, EULAR Endorsed MSUS Courses, as well as national and local MSUS Courses. The presented work gives indications on how to homogenise the teaching at the MSUS TTT Courses, thus resolving current discrepancies in the field.

EULAR-PReS points to consider for the use of imaging in the diagnosis and management of juvenile idiopathic arthritis in clinical practice.

To develop evidence based points to consider the use of imaging in the diagnosis and management of juvenile idiopathic arthritis (JIA) in clinical practice. The task force comprised a group of paediatric rheumatologists, rheumatologists experienced in imaging, radiologists, methodologists and patients from nine countries. Eleven questions on imaging in JIA were generated using a process of discussion and consensus. Research evidence was searched systematically for each question using MEDLINE, EMBASE and Cochrane CENTRAL. Imaging modalities included were conventional radiography, ultrasound, MRI, CT, scintigraphy and positron emission tomography. The experts used the evidence obtained from the relevant studies to develop a set of points to consider. The level of agreement with each point to consider was assessed using a numerical rating scale. A total of 13 277 references were identified from the search process, from which 204 studies were included in the systematic review. Nine points to consider were produced, taking into account the heterogeneity of JIA, the lack of normative data and consequent difficulty identifying pathology. These encompassed the role of imaging in making a diagnosis of JIA, detecting and monitoring inflammation and damage, predicting outcome and response to treatment, use of guided therapies, progression and remission. Level of agreement for each proposition varied according to the research evidence and expert opinion. Nine points to consider and a related research agenda for the role of imaging in the management of JIA were developed using published evidence and expert opinion.

EULAR recommendations for the use of imaging in the diagnosis and management of spondyloarthritis in clinical practice.

A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.

Ultrasound-guided synovial biopsy: a safe, well-tolerated and reliable technique for obtaining high-quality synovial tissue from both large and small joints in early arthritis patients.

OBJECTIVE: To determine the tolerability, safety and yield of synovial tissue in an early arthritis cohort using a minimally invasive, ultrasound (US)-guided, synovial biopsy technique in small, medium and large joints. METHODS: 93 sequential biopsy procedures were assessed from a total of 57 patients (baseline and 36 repeat biopsies at 6 months) recruited as part of the 'Pathobiology of Early Arthritis Cohort' study. Patients completed a tolerability questionnaire prior to and following the synovial biopsy procedure. The synovial biopsy was performed under US guidance with US images of the joint recorded prior to each procedure. Synovial tissue was harvested for immunohistochemistry and RNA extraction. RESULTS: Five different joint sites were biopsied (knee, elbow, wrist, metacarpal phalangeal and proximal interphalangeal). No significant complications were reported following the procedure. No difference in pain, swelling and stiffness of the biopsied joint from before and after the procedure was demonstrated. A median of 14 biopsy samples was retrieved from each procedure with 93% of biopsy procedures yielding good quality tissue. RNA yield was good in all joints and in repeat biopsies. Multivariant analysis demonstrated a significantly greater yield of RNA and graded tissue in relation to a high prebiopsy, grey-scale synovitis score (0-3, semiquantitative). CONCLUSIONS: A minimally invasive approach to synovial tissue harvesting, using US guidance, is both safe and well-tolerated by patients. Tissue quality/RNA yield is preserved in subsequent biopsies following therapeutic intervention. A high US grey-scale synovitis score is a predictor of good quality/quantity of tissue and RNA.

Defining enthesitis in spondyloarthritis by ultrasound: results of a Delphi process and of a reliability reading exercise.

OBJECTIVE: To standardize ultrasound (US) in enthesitis. METHODS: An initial Delphi exercise was undertaken to define US-detected enthesitis and its core components. These definitions were subsequently tested on static images taken from spondyloarthritis patients in order to evaluate their reliability. RESULTS: Excellent agreement (>80%) was obtained for including hypoechogenicity, increased thickness of the tendon insertion, calcifications, enthesophytes, erosions, and Doppler activity as core elementary lesions of US-detected enthesitis. US definitions were subsequently obtained for each elementary component. On static images, the intraobserver reliability showed a high degree of variability for the detection of elementary lesions, with kappa coefficients ranging from 0.13-1. The interobserver kappa values were variable, with the lowest kappa coefficient for enthesophytes (0.24) and the highest coefficient for Doppler activity at the enthesis (0.63). CONCLUSION: This is the first consensus-based US definition of enthesitis and its elementary components and the first step performed to ensure a higher degree of homogeneity and comparability of results between studies and in daily clinical work.

EFSUMB minimum training requirements for rheumatologists performing musculoskeletal ultrasound.

In order to optimize and standardize musculoskeletal ultrasonography education for rheumatologists, there is a need for competency assessments addressing the required training and practical and theoretical skills. This paper describes how these competency assessments for rheumatologists were developed and what they contain.

Clinical and ultrasound-based composite disease activity indices in rheumatoid arthritis: results from a multicenter, randomized study.

OBJECTIVE: To evaluate the metrologic properties of composite disease activity indices in rheumatoid arthritis (RA), utilizing information derived from clinical, gray-scale (GS), and power Doppler (PD) ultrasound examinations, and to assess the classification of patients according to disease activity using such indices. METHODS: This ancillary study utilized data from a multicenter, prospective, randomized, parallel-group study conducted in subjects with moderate RA randomized to receive etanercept and methotrexate (ETN + MTX) or usual care (various disease-modifying antirheumatic drugs [DMARDs]). In multimodal indices, the 28 swollen joint count was either supplemented or replaced by clinically nonswollen joints in which the presence of synovitis was detected either by GS and/or PD and was calculated according to the Disease Activity Score in 28 joints (DAS28) or the Simplified Disease Activity Index (SDAI). Reliability, external validity, and discriminative capacity were calculated at baseline/screening by intraclass correlation coefficient, Pearson's correlation, and standardized response mean, respectively. RESULTS: Data from 62 patients (mean ± SD age 53.8 ± 13.2 years, mean ± SD disease duration 8.8 ± 7.7 years, mean ± SD disease activity 4.6 ± 0.5 [DAS28] and 20.9 ± 5.9 [SDAI]) were analyzed, with 32 receiving ETN + MTX and 30 receiving DMARDs. The metrologic properties were at least as good for GS- and/or PD-based indices as for their clinical counterparts. Using GS- and PD-supplemented indices, an additional 67.8% and 32.3% of patients (DAS28-derived and SDAI-derived indices, respectively) could be classified as having high disease activity at the screening visit. CONCLUSION: Multimodal indices incorporating ultrasound and clinical data had similar metrologic properties to their clinical counterparts; certain indices allowed for a significantly larger number of patients to be classified to either high or moderate disease activity at the screening visit.

The reliability of musculoskeletal ultrasound in the detection of cartilage abnormalities at the metacarpo-phalangeal joints.

OBJECTIVE: To assess the reliability of ultrasound (US) in detecting cartilage abnormalities at the metacarpo-phalangeal (MCP) joints in people with cartilage pathology. METHODS: Nine expert ultrasonographers initially achieved consensus on definitions and scanning protocols. They then examined the second to fifth MCP joints of the dominant hand of eight people with hand osteoarthritis (OA). US examinations were conducted in two rounds, with independent blinded evaluations of cartilage lesions. Global cartilage abnormalities were assessed by applying a dichotomous (presence/absence) score; in addition, the following lesions were evaluated using the same scoring system: loss of anechoic structure and/or thinning of the cartilage layer, and irregularities and/or loss of sharpness of at least one cartilage margin. Reliability was assessed using kappa (k) coefficients. RESULTS: Thirty-two joints were examined. Intra-observer k values ranged from 0.52 to 1 for global cartilage abnormalities; k values ranged from 0.54 to 0.94 for loss of anechoic structure and/or thinning of cartilage layer and from 0.59 to 1 for irregularities and/or loss of sharpness of at least one cartilage margin. Values of k for inter-observer reliability were 0.80 for global cartilage abnormalities, 0.62 for loss of anechoic structure and/or thinning of cartilage layer, and 0.39 for irregularities and/or loss of sharpness of at least one cartilage margin. CONCLUSION: US is a reliable imaging modality for the detection of cartilage abnormalities in patients with cartilage pathology in the MCP joints. The analysis of specific cartilage measures showed more variable results that may be improved by modifying definitions and further standardization of US techniques.

Ultrasound evaluation of fluid in knee recesses at varying degrees of flexion.

OBJECTIVE: Various methods are utilized in daily practice to obtain optimal information on effusion in the knee. Our aim is to investigate which scanning position provides the best information about synovial fluid in the knee by using ultrasound and to evaluate the magnitude of difference for measuring synovial fluid in 3 major recesses (suprapatellar, medial parapatellar, and lateral parapatellar) of the knee according to various degrees of flexion. METHODS: Sonographers in 14 European centers documented bilateral knee joint ultrasound examinations on a total of 148 knee joints. The largest sagittal diameter of fluid was measured in scans corresponding to the 3 major recesses at different (0°, 15°, 30°, 45°, 60°, and 90°) degrees of flexion of the knee. The difference of measurement of effusion according to transducer position, knee position, and the interaction between them was investigated by analysis of variance followed by Tukey's test. RESULTS: No correlation was noted between patient characteristics and ultrasound detection of effusion. The sagittal diameter of synovial fluid in all 3 recesses was greatest at 30° flexion. Analysis of variance and Tukey's test revealed that the suprapatellar scan and 30° flexion is the best combination for detecting effusion as confirmed by receiver operator characteristic curve analysis. CONCLUSION: The suprapatellar scan of the knee in 30° flexion was the most sensitive position to detect fluid in knee joints. Sagittal diameter of fluid in all 3 recesses increased with the knee in the 30° flexed position as compared to the extended position.

Metrologic properties of ultrasound versus clinical evaluation of synovitis in rheumatoid arthritis: results of a multicenter, randomized study.

OBJECTIVE: To evaluate the intraobserver reliability, face validity, and discriminant capacity of different global ultrasound (US) scoring systems for measuring synovitis in rheumatoid arthritis (RA). METHODS: This study was ancillary to a 52-week, multicenter, prospective, randomized, open-label, parallel-group outpatient study conducted in patients with moderate RA who were randomized to receive either etanercept combined with methotrexate or various disease-modifying antirheumatic drugs. A total of 66 different synovitis scoring systems were constructed and evaluated, including 11 different joint combinations; data derived from clinical findings, gray-scale US, and power Doppler US (PDUS); and both binary counts and semiquantitative scores. RESULTS: Due to discontinuation of the trial, only 62 patients, a subset of the initially planned number of patients, were included in this study. Reliability was found to be better for gray-scale US and PDUS than for clinical evaluation of synovitis in patients with stable disease between the screening and baseline visits (range for intraclass correlation coefficient 0.6, 0.95 for gray-scale US and 0.56, 0.93 for PDUS versus 0.31, 0.75 for clinical indices). The median (range) difference in the discriminant capacities of clinical indices versus gray-scale US and versus PDUS was 0.25 (-0.64, 0.96) and -0.025 (-0.59, 0.53), respectively, in the period from baseline to 12 weeks. No relevant differences in metrologic properties were observed regarding the number and composition of joints between the different scoring systems. Our findings suggested that a simplified scoring system referring to gray-scale US and PDUS findings might be sufficient. CONCLUSION: Our findings indicate that gray-scale US and PDUS have better reliability than generally used clinical indices for evaluating synovitis in RA. PDUS has at least as good discriminant capacity as clinical assessment of synovitis for distinguishing between treatment arms.

Which knee and probe position determines the final diagnosis of knee inflammation by ultrasound? Results from a European multicenter study.

PURPOSE: To investigate which knee and probe position best identifies knee inflammation and to determine a cut-off level for abnormal synovial effusion. MATERIALS AND METHODS: 18 experienced sonographers (all rheumatologists) performed ultrasound examinations of the knee joint in patients with knee symptoms and in healthy controls. Each sonographer performed longitudinal suprapatellar ultrasound scans using 9 different configurations at each knee: Midline, parapatallar lateral and parapatellar medial from midline in neutral position (0°) with and without quadriceps muscle contraction and in 30° flexion of the knee. The presence of synovial effusion (SE), the effusion measured in millimeters and the presence of synovial hypertrophy (SH) was noted. RESULTS: A total of 298 knees of 149 subjects (129 patients and 20 controls) were examined. The detection of SH is more sensitive and specific than the detection of SE, independently of the knee and probe position, for the final diagnosis of abnormality. The detection of both synovial hypertrophy and effusion in the knee in neutral position (0°) with quadriceps contraction and with the probe in the midline position, are the best independent predictors for knee abnormalities. Knee effusion > 3.2 mm measured with the probe in the lateral aspect of the knee is the best diagnostic characteristics for predicting pathological SE. CONCLUSION: The best combination for detecting SH and SE is obtained by placing the probe in the midline position with the knee in 0° with quadriceps contraction. A cut-off value for pathological effusion may be obtained in the lateral aspect of the knee.