Validation and incorporation of digital entheses into a preliminary GLobal OMERACT Ultrasound DActylitis Score (GLOUDAS) in psoriatic arthritis.

OBJECTIVES: The main objective was to generate a GLobal OMERACT Ultrasound DActylitis Score (GLOUDAS) in psoriatic arthritis and to test its reliability. To this end, we assessed the validity, feasibility and applicability of ultrasound assessment of finger entheses to incorporate them into the scoring system. METHODS: The study consisted of a stepwise process. First, in cadaveric specimens, we identified enthesis sites of the fingers by ultrasound and gross anatomy, and then verified presence of entheseal tissue in histological samples. We then selected the entheses to be incorporated into a dactylitis scoring system through a Delphi consensus process among international experts. Next, we established and defined the ultrasound components of dactylitis and their scoring systems using Delphi methodology. Finally, we tested the interobserver and intraobserver reliability of the consensus- based scoring systemin patients with psoriatic dactylitis. RESULTS: 32 entheses were identified in cadaveric fingers. The presence of entheseal tissues was confirmed in all cadaveric samples. Of these, following the consensus process, 12 entheses were selected for inclusion in GLOUDAS. Ultrasound components of GLOUDAS agreed on through the Delphi process were synovitis, tenosynovitis, enthesitis, subcutaneous tissue inflammation and periextensor tendon inflammation. The scoring system for each component was also agreed on. Interobserver reliability was fair to good (κ 0.39-0.71) and intraobserver reliability good to excellent (κ 0.80-0.88) for dactylitis components. Interobserver and intraobserver agreement for the total B-mode and Doppler mode scores (sum of the scores of the individual abnormalities) were excellent (interobserver intraclass correlation coefficient (ICC) 0.98 for B-mode and 0.99 for Doppler mode; intraobserver ICC 0.98 for both modes). CONCLUSIONS: We have produced a consensus-driven ultrasound dactylitis scoring system that has shown acceptable interobserver reliability and excellent intraobserver reliability. Through anatomical knowledge, small entheses of the fingers were identified and histologically validated.

Enthesitis in patients with psoriatic arthritis treated with secukinumab or adalimumab: a post hoc analysis of the EXCEED study.

OBJECTIVES: To evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with PsA treated with secukinumab or adalimumab for 52 weeks. METHODS: In this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using non-responder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan-Meier analysis for time to resolution, and as-observed data for other outcomes. RESULTS: Enthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52. CONCLUSION: Secukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of IL-17 with secukinumab reduced clinical enthesitis similarly to TNF-α inhibition. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02745080.

Improved outcomes in rheumatoid arthritis with obesity after a weight loss intervention: randomized trial.

OBJECTIVE: To examine whether a weight loss intervention programme improves RA disease activity and/or musculoskeletal ultrasound synovitis measures in obese RA patients. METHODS: We conducted a proof-of-concept, 12-week, single-blind, randomized controlled trial of obese RA patients (BMI ≥ 30) with 28-joint DAS (DAS28) ≥ 3.2 and with evidence of power Doppler synovitis. Forty patients were randomized to the diet intervention (n = 20) or control group (n = 20). Diet intervention consisted of a hypocaloric diet of 1000-1500 kcal/day and high protein meal replacements. Co-primary outcomes included change in DAS28 and power Doppler ultrasound (PDUS)-34. Clinical disease activity, imaging, biomarkers, adipokines and patient-reported outcomes were monitored throughout the trial. Recruitment terminated early. All analyses were based on intent-to-treat for a significance level of 0.05. RESULTS: The diet intervention group lost an average 9.5 kg/patient, while the control group lost 0.5 kg (P < 0.001). Routine Assessment of Patient Index Data 3 (RAPID3) improved, serum leptin decreased and serum adiponectin increased significantly within the diet group and between the groups (all P < 0.03). DAS28 decreased, 5.2 to 4.2, within the diet group (P < 0.001; -0.51 [95% CI -1.01, 0.00], P = 0.056, between groups). HAQ-Disability Index (HAQ-DI) improved significantly within the diet group (P < 0.04; P = 0.065 between group). Ultrasound measures and the multi-biomarker disease activity score did not differ between groups (PDUS-34 -2.0 [95% CI -7.00, 3.1], P = 0.46 between groups). CONCLUSION: Obese RA patients on the diet intervention achieved weight loss. There were significant between group improvements for RAPID3, adiponectin and leptin levels, and positive trends for DAS28 and HAQ-DI. Longer-term, larger weight loss studies are needed to validate these findings, and will allow for further investigative work to improve the clinical management of obese RA patients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02881307.

Power doppler ultrasound signal predicts abnormal HDL function in patients with rheumatoid arthritis.

Active rheumatoid arthritis (RA) is associated with increased cardiovascular risk and impaired function of high-density lipoprotein (HDL). Previous work suggests that HDL may become dysfunctional through oxidative modifications within the RA joint. The current work evaluates an association of synovial power doppler ultrasound signal (PDUS) with HDL function and structure. Two open-label clinical therapeutic studies using PDUS as a disease outcome measure were included in this analysis, including a 12-month trial of subcutaneous abatacept in 24 RA patients and a 6-month trial of IV tocilizumab in 46 RA patients. Laboratory assays included assessments of HDL function and structure, HDL and total cholesterol levels, and a cytokine/chemokine panel. Patients with the highest baseline PDUS scores in both clinical studies, had worse HDL function, including suppression of paraoxonase 1 (PON1) activity as well as lower HDL-C levels. Associations between other disease assessments (DAS28 and CDAI) and HDL function/structure were noted but were generally of lesser magnitude and consistency than PDUS across the HDL profile. Treatment with tocilizumab for 6 months was associated with increases in cholesterol levels and improvements in the HDL function profile, which correlated with greater decreases in PDUS scores. Similar trends were noted following treatment with abatacept for 3 months. Higher baseline PDUS scores identified patients with worse HDL function. This data supports previous work suggesting a direct association of joint inflammation with abnormal HDL function.

The Role of Ultrasound in Research and Clinical Practice in Psoriatic Arthritis: Highlights From the GRAPPA Ultrasound Workshop.

Ultrasound (US) is a valuable imaging modality that can accurately identify relevant features of psoriatic arthritis (PsA), such as synovitis, tenosynovitis, and enthesitis. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Ultrasound Committee ran a workshop during the annual GRAPPA meeting that was held in July 2020. The group presented the following 3 topics: (1) the transition from psoriasis to PsA and the role of US; (2) the effect of biomechanical forces on the entheses in health and disease, and insight for PsA pathogenesis; and (3) differentiation of enthesitis from pain sensitization: use and limitations of clinical and sonographic evaluation of enthesitis. This article summarizes the key messages from this workshop.

Enthesitis in psoriatic arthritis (Part 2): imaging.

Enthesitis is a hallmark finding in PsA and may predate the onset of synovitis. Clinical examination of enthesitis provides no structural information, relies on eliciting tenderness at entheseal sites and may not be sensitive or specific. Soft tissue imaging techniques such as musculoskeletal ultrasound and MRI can depict ultrastructural and inflammatory changes. Although these imaging techniques are complimentary, ultrasound can image superficial entheses with high fidelity and examine vascularity with the use of Doppler but cannot image subchondral bone. MRI depicts bone and can visualize bone marrow edema as well as soft tissue edema. However, due to short relaxation times, entheseal structures are not easily differentiated. There has been increasing recognition of biomechanical confounding, especially since the majority of the entheses examined are in the lower extremity. Imaging entheseal indices are being developed to minimize the effect of body weight and activity. In the following article, contemporary concepts of entheses in relation to imaging will be reviewed as well as important confounders in assessing entheseal alterations. The role and limitations of imaging techniques will be discussed.

Visualization of Enthesitis by Ultrasound: a Key Diagnostic Tool in Spondyloarthropathy Diagnosis and Management.

PURPOSE OF REVIEW: The purpose of this review is to report on the current status of evaluation of enthesitis with sonography. Sonography can visualize peripheral entheses in great detail since most of them are superficial. Visualization of entheses has provided insights into the pathophysiology of enthesitis and highlighted the interconnectivity of stress dissipation mechanisms about the enthesis. The primary use of entheseal sonography presently revolves around diagnostic use. RECENT FINDINGS: There is increasing awareness of biomechanical confounders that lead to entheseal changes, which are more prevalent in males, patients with higher body mass index, and those who are more active-though there are several approaches to mitigate biomechanical confounders in sonographic evaluation. Entheseal sonography may also provide prognostic information in predicting the severity of axial syndesmophyte formation. Although entheseal outcome scoring systems are available, there is sparse data on its use as an outcome tool, and hence, this is a fertile area for future research.

Development and Validation of a Sonographic Enthesitis Instrument in Psoriatic Arthritis: The GRAPPA Diagnostic Ultrasound Enthesitis Tool (DUET) Project.

Enthesitis is a key feature in psoriatic arthritis (PsA) and may be the initial site of musculoskeletal inflammation in patients with PsA. Ultrasound (US) optimizes the detection of enthesitis, but the lack of a validated sonographic enthesitis scoring system for PsA limits the ability to conduct US-based studies of approaches to improve the early diagnosis of PsA. Creating a sonographic enthesitis scoring system that reliably identifies PsA at early stages is an important step in optimizing early diagnosis and encouraging timely interventions that will ultimately improve longterm outcomes for patients with PsA. The Group for Research and Assessment of Psoriasis and PsA (GRAPPA) US working group has set a goal of improving the evaluation of enthesitis in patients with PsA by using US through the development of a Diagnostic Ultrasound Enthesitis Tool (DUET). This article summarizes the proposed DUET study design and methodology as discussed during the 2019 GRAPPA annual meeting in Paris, France.

The GRAPPA Sonographic Enthesitis Workshop.

Enthesitis is a key feature in psoriatic arthritis (PsA) and may be the initial site of musculoskeletal inflammation in patients with PsA. Ultrasound (US) could improve the accuracy of clinical enthesitis assessment, but at present no consensus exists on a global sonographic enthesitis scoring method that can evaluate the extent of enthesitis at the patient level. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) US Working Group has set up a goal to optimize the evaluation of enthesitis in patients with PsA using US through the development and validation of new instruments using a combined data-driven and expert opinion-driven approach. This article summarizes the GRAPPA US Working Group's recent activities and focuses on a 2-day workshop that the group held following the annual 2018 GRAPPA meeting in Toronto, Ontario, Canada.

Options for Assessing Joints and Entheses in Psoriatic Arthritis by Ultrasonography and Magnetic Resonance Imaging: How to Move Forward.

Psoriatic arthritis (PsA) is a heterogeneous disease with various manifestations of musculoskeletal inflammation. Recent advances in imaging, including ultrasound (US) and magnetic resonance imaging (MRI), allow for the accurate evaluation of the extent of inflammation and damage in the peripheral joints, spine, and entheses. The development and validation of outcome measures are critical steps in creating standardized evaluations of musculoskeletal inflammation and damage in psoriatic patients. At the 2017 meeting of the Group for Research and Assessment of Psoriasis and PsA (GRAPPA), recent work on outcome measures from the GRAPPA US and MRI working groups was summarized. The GRAPPA US group has been developing and validating a sonographic enthesitis scoring system in PsA. The GRAPPA MRI group focuses on the evaluation of whole-body MRI for the assessment of musculoskeletal inflammation in the joints and entheses in patients with PsA.

The 2017 EULAR standardised procedures for ultrasound imaging in rheumatology.

BACKGROUND: In 2001, the European League Against Rheumatism developed and disseminated the first guidelines for musculoskeletal (MS) ultrasound (US) in rheumatology. Fifteen years later, the dramatic expansion of new data on MSUS in the literature coupled with technological developments in US imaging has necessitated an update of these guidelines. OBJECTIVES: To update the existing MSUS guidelines in rheumatology as well as to extend their scope to other anatomic structures relevant for rheumatology. METHODS: The project consisted of the following steps: (1) a systematic literature review of MSUS evaluable structures; (2) a Delphi survey among rheumatologist and radiologist experts in MSUS to select MS and non-MS anatomic structures evaluable by US that are relevant to rheumatology, to select abnormalities evaluable by US and to prioritise these pathologies for rheumatology and (3) a nominal group technique to achieve consensus on the US scanning procedures and to produce an electronic illustrated manual (ie, App of these procedures). RESULTS: Structures from nine MS and non-MS areas (ie, shoulder, elbow, wrist and hand, hip, knee, ankle and foot, peripheral nerves, salivary glands and vessels) were selected for MSUS in rheumatic and musculoskeletal diseases (RMD) and their detailed scanning procedures (ie, patient position, probe placement, scanning method and bony/other landmarks) were used to produce the App. In addition, US evaluable abnormalities present in RMD for each anatomic structure and their relevance for rheumatology were agreed on by the MSUS experts. CONCLUSIONS: This task force has produced a consensus-based comprehensive and practical framework on standardised procedures for MSUS imaging in rheumatology.

International Consensus for ultrasound lesions in gout: results of Delphi process and web-reliability exercise.

OBJECTIVE: To produce consensus-based definitions of the US elementary lesions in gout and to test their reliability in a web-based exercise. METHODS: The process consisted of two steps. In the first step a written Delphi questionnaire was developed from a systematic literature review and expert international consensus. This collated information resulted in four statements defining US elementary lesions: double contour (DC), tophus, aggregates and erosion. The Delphi questionnaire was sent to 35 rheumatology experts in US, asking them to rate their level of agreement or disagreement with each statement. The second step tested the reliability by a web-exercise. US images of both normal and gouty elementary lesions were collected by the participants. A facilitator then constructed an electronic database of 110 images. The database was sent to the participants, who evaluated the presence/absence of US elementary lesions. A group of 20 images was displayed twice to evaluate intra-reader reliability. RESULTS: A total of 32 participants responded to the questionnaires. Good agreement (>80%) was obtained for US definitions on DC, tophus, aggregates and erosion in the Delphi exercise after three rounds. The reliability on images showed inter-reader κ values for DC, tophus, aggregates, erosion findings of 0.98, 0.71, 0.54 and 0.85, respectively. The mean intra-reader κ values were also acceptable: 0.93, 0.78, 0.65 and 0.78, respectively. CONCLUSION: This, the first consensus-based US definition of elementary lesions in gout, demonstrated good reliability overall. It constitutes an essential step in developing a core outcome measurement that permits a higher degree of homogeneity and comparability between multicentre studies.

Musculoskeletal ultrasound training and competency assessment program for rheumatology fellows.

OBJECTIVES: The purpose of this study was to establish standards for musculoskeletal ultrasound competency through knowledge and skills testing using criterion-referenced methods. METHODS: Two groups of rheumatology fellows trained in musculoskeletal ultrasound through a standardized curriculum, which required submission of ultrasound studies for review over 8 months. Both groups then completed written and practical examinations in musculoskeletal ultrasound. Instructors, advanced users, and intermediate users of musculoskeletal ultrasound served as comparison groups. A passing score (competency) was established for the written examination by the Angoff procedure and for the practical examination by the borderline method. RESULTS: Thirty-eight fellows (19 in each group) took the final examination. Five fellows failed the written examination, and 1 failed the practical examination, whereas none of the advanced users failed. Written examination scores did not differ between the two fellow groups (74% versus 70%; P > .05), were reliable, and were able to discriminate between the intermediate and advanced groups. Practical and written examination results correlated in both groups (first group, r = 0.70; P = .0008; second group, r = 0.59; P = .009). CONCLUSIONS: Criterion-referenced methods were used for the first time to determine fellow musculoskeletal ultrasound competency. The examination used to determine competency was reproducible, was reliable, and could differentiate musculoskeletal ultrasound users with different levels of experience. Most rheumatology fellows completing our program passed the written and practical examinations, suggesting achievement of basic musculoskeletal ultrasound competency.

Seeing is believing: Smart use of musculoskeletal ultrasound in rheumatology practice.

Musculoskeletal ultrasonography has become an increasingly valuable tool as a complement to the physical exam in rheumatology practice. Its point-of-care access, low cost, safety, portability, and reliability in trained hands, make this technique especially useful in patients with inflammatory arthritis. Growing evidence has demonstrated the value of musculoskeletal ultrasound in the detection of inflammatory and structural changes in patients with joint pain without obvious joint swelling, in differentiating various inflammatory diagnoses, in the monitoring of inflammatory arthritis, and interventional procedures. The potential role of ultrasound guiding treat-to-target strategies or tapering treatment in inflammatory arthritis requires further research. However, musculoskeletal ultrasound can also have pitfalls and limitations that a clinician should be aware of.

Developing Ultrasound Measures for the Early Diagnosis of Psoriatic Arthritis.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) ultrasound (US) steering committee provided an update at GRAPPA's 2022 annual meeting on activities to enable earlier diagnosis of psoriatic arthritis. An update of the Diagnostic Ultrasound Enthesitis Tool (DUET) study included preliminary reliability results for US enthesitis elementary lesions. Common scanning pitfalls were reviewed. New projects included widening the scope of US beyond large entheses and validating small point-of-care US probes to evaluate enthesitis.

Musculoskeletal Ultrasound in Childhood Arthritis Limited Examination: A Comprehensive, Reliable, Time-Efficient Assessment of Synovitis.

OBJECTIVE: To develop and initially validate a comprehensive pediatric musculoskeletal ultrasound (MSUS) joint-specific scoring system, and to determine the minimum number of joints needed to identify active disease. METHODS: A semiquantitative scoring system was developed by consensus and initially validated by interrater reliability using intraclass correlation coefficients (ICCs). Subsequently, newly diagnosed juvenile idiopathic arthritis patients with an active joint count of >4 had a 42-joint MSUS performed at baseline and 3 months using this protocol. A minimum set of joints needed to identify all patients with synovitis on MSUS was obtained through a data reduction process. Spearman's correlation (rs ) was calculated to determine the association between MSUS findings and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10). Standardized response means (SMRs) were used to assess change over time. RESULTS: The final joint-specific scoring system revealed an excellent interrater reliability (ICC 0.81-0.96) for all joints. Thirty patients were enrolled. Scanning 5 joints bilaterally (wrists, second and third metacarpophalangeal joints, knees and ankles) captured 100% of children with B-mode synovitis and had moderate correlation with the cJADAS10 at baseline (rs  = 0.45). Mean ultrasound scores at baseline and follow-up were 28.3 and 22.3, with an SRM of 0.69 (P = 0.002) for 42 joints, and 36 and 27.7, with an SRM of 0.76 (P = 0.003) for the reduced joints, respectively. CONCLUSION: A limited MSUS examination called musculoskeletal ultrasound in childhood arthritis limited examination (MUSICAL) captures all patients with active synovitis, and our new joint-specific scoring system is highly reliable and sensitive to change.

Management of Dactylitis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: This literature review aimed to identify the most efficacious current interventions for dactylitis and provide up-to-date scientific evidence to support the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations on the management of psoriatic arthritis. METHODS: Original articles published from 2013 to 2020, registered in MEDLINE, Embase, and Cochrane Library, describing interventional trials and reporting dactylitis-related outcomes were included. The 20 members of the GRAPPA dactylitis group were divided into 9 subgroups according to treatment, and members of each group independently extracted data from articles/abstracts corresponding to their group by using a standardized data extraction form. RESULTS: Forty-nine publications were analyzed, representing 40 randomized clinical trials (RCTs) and including 16,752 patients. Dactylitis was assessed as a secondary outcome in 97.5% of these trials and more than 40% of RCTs did not employ a specific dactylitis measure or instrument. CONCLUSION: The emergence of agents with novel mechanisms of action in recent years, such as interleukin 17 (IL-17), IL-12/23, IL-23, and Janus kinase inhibitors, has significantly expanded the available treatment options for dactylitis. This article points out the lack of consensus regarding dactylitis assessment and the paucity of data concerning the effect of local steroid injections, nonsteroidal antiinflammatory drugs, and conventional disease-modifying antirheumatic drugs. Clinical trials evaluating the effect of these traditional and low-cost medications used to treat dactylitis should be encouraged.

Toward a Sonographic Composite Index for Diagnosis in Psoriatic Arthritis: Highlights From the GRAPPA Ultrasound Workshop.

The ability to visualize musculoskeletal structures with high-resolution ultrasound is an asset to understanding the complexity of psoriatic arthritis (PsA). During the 2021 Annual Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) meeting, 3 topics were presented and discussed in the ultrasound workshop: (1) the progress on the Diagnostic Ultrasound Enthesitis Tool (DUET) project; (2) the sonographic evaluation of joints in PsA-GRAPPA joint project; and (3) extrasynovial lesions in PsA. The ultrasound group aims to develop sonographic tools that are feasible and can be used in standard care to diagnose PsA early. The discussions around these topics will shape the group's work toward developing a composite index to diagnose PsA early.

Optimizing Reliability of Real-Time Sonographic Examination and Scoring of Joint Synovitis in Rheumatoid Arthritis.

OBJECTIVE: Musculoskeletal ultrasound real-time image acquisition and scoring are complex, and many factors affect reliability. Static image reliability does not guarantee real-time scoring. This study aimed to identify factors and solutions to improve real-time scoring reliability for the grey scale and power Doppler evaluation of synovitis. We also report on using a novel musculoskeletal ultrasound synovitis rule-based scoring atlas. METHODS: In four stages, we evaluated inter- and intra-reader reliability among three ultrasonographers (US1-3). Intra- and inter-reader reliability was calculated using weighted-kappa, intraclass correlation coefficient, and Spearman correlation. Reliability statistics were compared between stages using permutation tests to compute empirical distributions for differences in those statistics. At each stage, factors that diminished reliability were identified and addressed. After intensive reliability exercises, a RA MSUS atlas with in-depth scoring rules was generated to improve interpretive reliability. RESULTS: The three ultrasonographers had good to excellent intra-reader reliability for real-time acquisition scoring over 2432 views (weighted kappa 0.52-0.80, intraclass correlation coefficient 0.59-0.86, and Spearman correlation 0.64-0.86). Inter-reader reliability was good to excellent between US1/US2 and US1/US3 (weighted kappa 0.51-0.66, intraclass correlation coefficient 0.66-0.75, Spearman correlation 0.59-0.73). US1 achieved significant improvement in intra-reader reliability from stage 1 to stage 2 (p<0.05, weighted-kappa 0.63 to 0.80, intraclass correlation coefficient 0.71 to 0.86, Spearman 0.67 to 0.86) with use of the atlas.  Conclusion: This rheumatoid arthritis musculoskeletal ultrasound study addressed complex factors affecting musculoskeletal ultrasound acquisition-scoring reliability. Systematic identification and amelioration of many factors and using a novel rule-based scoring atlas significantly improved intra-reader reliability.