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.

Reliability assessment of the definition of ultrasound enthesitis in SpA: results of a large, multicentre, international, web-based study.

OBJECTIVES: To investigate the reliability of the OMERACT US Task Force definition of US enthesitis in SpA. METHODS: In this web exercise, based on the evaluation of 101 images and 39 clips of the main entheses of the lower limbs, the elementary components included in the OMERACT definition of US enthesitis in SpA (hypoechoic areas, entheseal thickening, power Doppler signal at the enthesis, enthesophytes/calcifications, bone erosions) were assessed by 47 rheumatologists from 37 rheumatology centres in 15 countries. Inter- and intra-observer reliability of the US components of enthesitis was calculated using Light's kappa, Cohen's kappa, Prevalence And Bias Adjusted Kappa (PABAK) and their 95% CIs. RESULTS: Bone erosions and power Doppler signal at the enthesis showed the highest overall inter-reliability [Light's kappa: 0.77 (0.76-0.78), 0.72 (0.71-0.73), respectively; PABAK: 0.86 (0.86-0.87), 0.73 (0.73-0.74), respectively], followed by enthesophytes/calcifications [Light's kappa: 0.65 (0.64-0.65), PABAK: 0.67 (0.67-0.68)]. This was moderate for entheseal thickening [Light's kappa: 0.41 (0.41-0.42), PABAK: 0.41 (0.40-0.42)], and fair for hypoechoic areas [Light's kappa: 0.37 (0.36-0.38); PABAK: 0.37 (0.37-0.38)]. A similar trend was observed in the intra-reliability exercise, although this was characterized by an overall higher degree of reliability for all US elementary components compared with the inter-observer evaluation. CONCLUSIONS: The results of this multicentre, international, web-based study show a good reliability of the OMERACT US definition of bone erosions, power Doppler signal at the enthesis and enthesophytes/calcifications. The low reliability of entheseal thickening and hypoechoic areas raises questions about the opportunity to revise the definition of these two major components for the US diagnosis of enthesitis.

Disease activity at the entheses and joints are correlated in psoriatic arthritis when explored with ultrasound.

OBJECTIVES: The aim of this study is to explore the link between the severity of the joint and entheses involvement in psoriatic arthritis (PsA) using musculoskeletal ultrasound (US). METHODS: PsA patients from two centres in the Psoriatic Arthritis International Database (PsArt-ID) (n=126) underwent an ultrasound assessment of 46 joints and 12 large entheses. The correlation between joint and enthesitis scores on the US was analysed, in addition to the clinical indices versus the US. RESULTS: Grey-scale (GS) synovitis score for the joints was moderately correlated with the total enthesitis score (r=0.410, p<0.001). The Global Outcome Measure in Rheumatology in Clinical Trials-European League Against Rheumatism Synovitis Score (GLOESS) score was also found in correlation with the total enthesitis score (r=0.400, p<0.001). The link between the US and clinical examination findings only showed a poor correlation between swollen joint counts (SJC) and joint-US scores (r=0.298, p=0.001 for GLOESS). Assessment of the entheses on US showed a poor-moderate correlation between the entheseal damage scores and tender joint counts (TJC) (r=0.217, p=0.018) and SJC (r=0.326, p<0.001). In terms of the clinical examination and activity parameters, none of the clinical parameters and acute phase reactants were correlated to Leeds Enthesitis Index. CONCLUSIONS: Our study showed a link between the severity of the sonographic findings in the joints and the entheses. Imaging using US to assess enthesitis in clinical trials may improve our understanding on the role of enthesitis in disease pathogenesis.

The transition from enthesis physiological responses in health to aberrant responses that underpin spondyloarthritis mechanisms.

PURPOSE OF REVIEW: Despite immunology and translational therapeutics advances in inflammatory arthritis over the past two decades, the enthesis, which is the epicentric of the spondyloarthritis family pathological process, retains many mysteries because of tissue inaccessibility that hampers direct immune study. As entheses are subject to almost continuous mechanical stress and spondyloarthritis is linked to microdamage or injury and joint stress, it is cardinal to understand the physiological changes occurring within the entheses not only to be able to differentiate disease from health but also to understand the transition normal physiology break down and its merges into spondyloarthritis-related disease. RECENT FINDINGS: Imaging has played a major role in understanding the enthesis in human. Remarkable insights from enthesis functioning and microdamage in normal and with ageing including those linked to body mass index is emerging. The impact of mechanical stress and degenerative conditions on the development of the secondary entheseal vascular changes is not understood. Of note, ultrasound studies in psoriasis have shown higher power Doppler changes compared to controls pointing towards a role for vascular changes in the development of enthesitis in psoriatic arthritis. SUMMARY: The literature pertaining to normal entheses changes with age, microdamage and vascular changes in health is providing a roadmap for understanding of the enthesis and its potential role in evolution of spondyloarthritis including psoriatic arthritis.

PsART-ID inception cohort: clinical characteristics, treatment choices and outcomes of patients with psoriatic arthritis.

OBJECTIVES: Our aim is to understand clinical characteristics, real-life treatment strategies, outcomes of early PsA patients and determine the differences between the inception and established PsA cohorts. METHODS: PsArt-ID (Psoriatic Arthritis- International Database) is a multicentre registry. From that registry, patients with a diagnosis of PsA up to 6 months were classified as the inception cohort (n==388). Two periods were identified for the established cohort: Patients with PsA diagnosis within 5-10 years (n = 328), ≥10 years (n = 326). Demographic, clinical characteristics, treatment strategies, outcomes were determined for the inception cohort and compared with the established cohorts. RESULTS: The mean (s.d.) age of the inception cohort was 44.7 (13.3) and 167/388 (43.0%) of the patients were male. Polyarticular and mono-oligoarticular presentations were comparable in the inception and established cohorts. Axial involvement rate was higher in the cohort of patients with PsA ≥10 years compared with the inception cohort (34.8% vs 27.7%). As well as dactylitis and nail involvement (P = 0.004, P = 0.001 respectively). Both enthesitis, deformity rates were lower in the inception cohort. Overall, 13% of patients in the inception group had a deformity. MTX was the most commonly prescribed treatment for all cohorts with 10.7% of the early PsA patients were given anti-TNF agents after 16 months. CONCLUSION: The real-life experience in PsA patients showed no significant differences in the disease pattern rates except for the axial involvement. The dactylitis, nail involvement rates had increased significantly after 10 years from the diagnosis and the enthesitis, deformity had an increasing trend over time.

Disease characteristics of psoriatic arthritis patients may differ according to age at psoriasis onset: cross-sectional data from the Psoriatic Arthritis-International Database.

OBJECTIVES: To explore the impact of early versus late-onset psoriasis (PsO) on the disease characteristics of psoriatic arthritis (PsA) in a large-multicentre cohort. METHODS: The data from a multicentre psoriatic arthritis database was analysed. Patients were grouped according to age at psoriasis onset (early onset; <40 years of age, late-onset; >40 years of age) and disease characteristics of the groups were compared by adjusting for BMI and PsA duration, where necessary. RESULTS: At the time of analyses, 1634 patients were recruited [62.8% females; early onset 1108 (67.8%); late-onset, 526 (32.2%)]. The late-onset group was more over-weight [66.8% vs. 86.8%, p<0.001; adjusted for age - aOR 1.55 (1.11-2.20; 95% CI)]. The early onset group had more scalp psoriasis at onset (56.7% vs. 43.0%, p<0.001), whereas extremity lesions were more common in the late-onset group (63.8% vs. 74.2%, p<0.001). Axial disease in males and psoriatic disease family history in females were significantly higher in the early onset group [38.0% vs. 25.4%; p=0.005; adjusted for PsA duration - aOR 1.76 (1.19-2.62; 95% CI) / 39.5% vs. 30.1%; p=0.003; OR 1.51 (1.15-1.99; 95% CI), respectively]. Psoriatic disease activity parameters, patient-physician reported outcomes and HAQ-DI scores were similar in both groups. CONCLUSIONS: Clinical features of PsA may be affected by the age at onset of PsO. Different genetic backgrounds in early and late-onset PsO may be driving the differences in psoriasis and PsA phenotypes.

Power Doppler enhancement of accessory pulleys confirming disease localization in psoriatic dactylitis.

OBJECTIVE: The digital accessory pulleys are highly mechanically stressed mini-entheses that are thickened in patients with a history of PsA-related dactylits. This study explored whether these pulleys are involved in PsA dactylitis as assessed by intra-pulley US power Doppler changes. METHODS: Fifty-eight PsA patients with dactylitis had US of the second to fourth digits for pulleys of the dactylitic and contralateral digits. The Leeds Dactylometer was used for thickness measurement. The presence of digital pain, tenderness, and swelling in the dactylitis finger and in the contralateral side was evaluated. RESULTS: We recruited 34 patients with acute and 24 patients with chronic dactylitis, 45/58 (77%) of which had tenderness on clinical assessment. Intra-pulley power Doppler was more frequently found in the dactylitic digits compared with contralateral sides and linked to A1, A2 and A4 pulleys thickening [power Doppler signals in A1 pulley (51%), A2 (22%) and A4 (12%) in dactylitic digit; compared with 1 A1, A2 and A4 pulleys each in the contralateral side (1.7%)]. Almost all cases had peri-tendinous oedema, and 82.6% of dactylitic digits had flexor tenosynovitis with power Doppler signals in 65.2% of flexor tendons. CONCLUSION: Despite their small size and relatively avascular, the accessory pulleys exhibit power Doppler change in active Psoriatic dactylitis, supporting a pivotal role in dactylitis-related tenosynovitis and extra-tendinous disease.

The role of obesity on inflammation and damage in spondyloarthritis: a systematic literature review on body mass index and imaging.

OBJECTIVES: The objective of this systematic literature review was to evaluate the effect of obesity and/or body mass index (BMI) on radiographic findings of spondyloarthritis (SpA) for both axial and peripheral inflammation and damage. METHODS: Medline, Embase and Cochrane databases were screened on February 13, 2017. The titles and the abstracts were independently screened by two investigators. Articles that have evaluated the link between BMI and plain radiography, ultrasound (US) and magnetic resonance imaging (MRI) in SpA were investigated. RESULTS: The literature search resulted in 613 articles, 5 of which met the inclusion criteria for the final analysis. Studies mostly investigated the effect of BMI on axial disease and mostly in ankylosing spondylitis. The major finding was that a higher BMI was closely related with new bone formation including syndesmophytes, enthesophytes and also a higher modified Stoke Ankylosing Spondylitis Spinal Score. Fewer studies looked at the effect of BMI on the peripheral enthesis which found a moderately positive correlation between the Madrid Sonographic Enthesitis Index for enthesitis on US and BMI. Gender was a significant factor to influence this link with one study correlated US enthesophyte scores with BMI in males but not in females. No studies on MRI met the inclusion criteria to be included. CONCLUSIONS: BMI is linked to both axial and peripheral new bone formation and entheseal inflammation by imaging, as supported by the limited number of studies in the literature. Its effect on the sacroiliac joint and spinal inflammation is not clear as MRI studies are lacking.

From Psoriasis to Psoriatic Arthritis: Insights from Imaging on the Transition to Psoriatic Arthritis and Implications for Arthritis Prevention.

PURPOSE OF REVIEW: To describe the recent advances in the field towards the prevention and early recognition of Psoriatic Arthritis (PsA). RECENT FINDINGS: Defining the preclinical phase of PsA remains challenging since up to 50% of subjects with psoriasis have subclinical imaging enthesopathy, but many of these do not progress to PsA. Nevertheless, there is evidence that subjects with subclinical imaging enthesopathy are at increased risk of developing PsA. In recent years, it has been shown that both PsA and anti-citrullinated protein antibodies (ACPA) positive rheumatoid arthritis (RA) are characterized by a subclinical phase of non-specific or brief duration arthralgia with shared imaging features accounting for joint symptomatology. Sonographically determined tenosynovitis and enthesitis are the key imaging features present in non-specific PsO arthralgia that are at risk of future PsA development. Furthermore, the early phases of PsA are complicated by factors including body mass index (BMI), which is a risk factor for PsA, but BMI is also associated with imaging abnormalities on enthesopathy. Fully disentangling these clinical and imaging factors will be important for enrichment for imminent PsA so that disease prevention strategies can be investigated. Psoriasis patients with arthralgia have a higher prevalence of tenosynovitis and imaging enthesopathy is at higher risk of transitioning to overt PsA.

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.

Comparing patient-perceived and physician-perceived remission and low disease activity in psoriatic arthritis: an analysis of 410 patients from 14 countries.

BACKGROUND: The objective was to compare different definitions of remission and low disease activity (LDA) in patients with psoriatic arthritis (PsA), based on both patients' and physicians' perspectives. METHODS: In ReFlap (Remission/Flare in PsA; NCT03119805), adults with physician-confirmed PsA and >2 years of disease duration in 14 countries were included. Remission was defined as very low disease activity (VLDA), Disease Activity index for PSoriatic Arthritis (DAPSA) ≤4, and physician-perceived and patient-perceived remission (specific question yes/no), and LDA as minimal disease activity (MDA), DAPSA <14, and physician-perceived and patient-perceived LDA. Frequencies of these definitions, their agreement (prevalence-adjusted kappa), and sensitivity and specificity versus patient-defined status were assessed cross-sectionally. RESULTS: Of 410 patients, the mean age (SD) was 53.9 (12.5) years, 50.7% were male, disease duration was 11.2 (8.2) years, 56.8% were on biologics, and remission/LDA was frequently attained: respectively, for remission from 12.4% (VLDA) to 36.1% (physician-perceived remission), and for LDA from 25.4% (MDA) to 43.9% (patient-perceived LDA). Thus, patient-perceived remission/LDA was frequent (65.4%). Agreement between patient-perceived remission/LDA and composite scores was moderate to good (kappa range, 0.12-0.65). When patient-perceived remission or LDA status is used as reference, DAPSA-defined remission/LDA and VLDA/MDA had a sensitivity of 73.1% and 51.5%, respectively, and a specificity of 76.8% and 88.0%, respectively. Physician-perceived remission/LDA using a single question was frequent (67.6%) but performed poorly against other definitions. CONCLUSION: In this unselected population, remission/LDA was frequently attained. VLDA/MDA was a more stringent definition than DAPSA-based remission/LDA. DAPSA-based remission/LDA performed better than VLDA/MDA to detect patient-defined remission or remission/LDA. Further studies of long-term outcomes are needed.

Greater magnitude of entheseal microdamage and repair in psoriatic arthritis compared with ankylosing spondylitis on ultrasound.

Objectives: AS and PsA share clinical and immunological features centred on enthesitis. However, a strong association between PsA and preceding injury has been recognized. The aim of this study was to test the hypothesis that the entheseal damage seen by US is commoner in PsA patients than in AS patients. Methods: Seventy-nine AS and 85 PsA patients had US scans of 1640 entheses to calculate entheseal inflammation (hypoechogenicity, thickening and Doppler) and damage scores (calcifications, enthesophytes and erosions). Regression modelling was done to evaluate the effect of diagnoses on outcomes, controlling for age, gender, BMI, clinical enthesitis, HLA-B27, and anti-TNF use. Results: Both inflammation and damage scores on US were correlated with BMI (r = 0.392; r = 0.320) and age (r = 0.308; r = 0.538) (P < 0.001), and men had higher inflammation scores than women [12.3 (7.5) vs 8.9 (7.3), P = 0.001]. In multivariate analysis, despite similar (anti-TNF-treated patients) or slightly less inflammation (anti-TNF-naïve patients) in the PsA group, they had 4.22 times more US damage than their counterparts with AS. The difference was even higher in the anti-TNF-naïve patients (5.6 times). Conclusion: On US assessment, PsA patients have greater entheseal insertion damage scores compared with AS, suggesting potential differences in tissue repair, immunobiology or response to injury at insertions.

What are the main barriers to achieve minimal disease activity in psoriatic arthritis in real life?

OBJECTIVES: Minimal disease activity (MDA) is an important target in patients with psoriatic arthritis (PsA), however it is also criticised for having a low threshold for patient reported outcomes (PRO).The aim of the study was to assess the prevalence of MDA and its components in patients with PsA and to evaluate disease characteristics and patterns in patients with or without MDA (MDA+ or MDA-). METHODS: PsArt-ID (Psoriatic Arthritis-International Database) is a prospective, multicentre web-based registry. PsA patients who had at least 1 year of disease duration and had full data for MDA were included for this analysis (n=317). Patients were considered in MDA+ when they met at least 5/7 of the MDA criteria. RESULTS: MDA was achieved in 46% patients. Within MDA- patients, body surface area (51.2%) and swollen joint count (53.5%) domains could still be achieved in the majority and 93.5% of them had no enthesitis using the Leeds enthesitis index. Of 170 patients with MDA-, 90 patients did not fulfill all 3 PROs of MDA. Mono-arthritis subtype (RR: 2.01), absence of enthesitis (RR: 1.570) and absence of distal interphalangeal (DIP) joint disease (RR: 1.1) were associated with higher probability of achieving MDA. CONCLUSIONS: The MDA criteria provide an objective target for treatment in trials and clinical practice; however, in real life PROs are the most significant barriers to achieve MDA. The presence of DIP joints disease makes it difficult to reach MDA due to active PROs.

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.

'Deep Koebner' phenomenon of the flexor tendon-associated accessory pulleys as a novel factor in tenosynovitis and dactylitis in psoriatic arthritis.

OBJECTIVES: Skin and joint involvement in psoriasis (PsO) and psoriatic arthritis (PsA) are thought to relate to the so-called Koebner response. Given that dactylitis is non-randomly distributed in the digits, this study tested the hypothesis that the accessory pulleys linked to the flexor tendons were thickened in PsA and thus exhibited koebnerisation. METHODS: Ninety-six subjects (27 PsA, 27 rheumatoid arthritis (RA), 23 PsO and 19 healthy controls (HCs)) were enrolled. The A1, A2 and A4 pulley thickness was measured using a high-resolution probe (22 MHz). All patients were in remission or low disease activity with current dactylitis being excluded. RESULTS: Within 864 pulleys investigated, patients with PsA had thicker pulleys in every digit compared with both RA (P<0.001 and P=0.003) and HCs (P<0.001). RA and PsO groups had some pulleys in some digits thicker than HCs whereas some others were comparable. The second digit A1 pulley thickness was higher in patients with PsA with previous dactylitis (P=0.020). More pulleys were thickened in the PsA group (165/243, 68%) than RA (41/243, 17%; P<0.001) and HCs (13/171, 7.6%; P<0.001). CONCLUSIONS: In established PsA, the accessory pulleys are thickened compared with RA, PsO or HCs and especially in subjects with a history of dactylitis. These findings implicate the involvement of pulleys in PsA-related tenosynovitis and dactylitis supporting the idea of deep koebnerisation in dactylitis and sites of high physical stress.

Similar subclinical enthesitis in celiac and inflammatory bowel diseases by ultrasound suggests a gut enthesis axis independent of spondyloarthropathy spectrum.

Objective: Higher subclinical enthesitis on US has been reported in IBD and celiac disease, separately. The objective of this study was to compare IBD and celiac disease for enthesitis on US. Higher enthesitis scores in IBD compared with celiac disease would support a shared pathogenic mechanism between IBD and spondyloarthritis, whereas similar scores may suggest a general impact of gut inflammation on the enthesis. Methods: Patients with IBD, celiac disease and healthy controls (HCs) were recruited and 12 entheses were scanned by US, blind to the diagnosis and clinical assessment. Elementary lesions for enthesitis were scored on a scale between 0 and 3, for inflammation, damage and total US scores. Results: A total of 1260 entheses were scanned in 44 patients with celiac disease, 43 patients with IBD and 18 HCs. The three groups were matched for age and BMI. Patients with celiac disease and IBD had higher inflammation scores than HCs [10.4 (6.5), 9.6 (5.4) and 5.6 (5.2), respectively, P = 0.007) whereas damage scores were similar. Both age and BMI had significant effects on the entheseal scores, mostly for inflammation scores but when controlling for these the US enthesopathy scores were still higher in celiac disease and IBD. Conclusion: The magnitude of subclinical enthesopathy scores is similar between celiac disease and IBD in comparison with HCs. These findings suggest that the common factor between both diseases and enthesopathy is abnormal gut permeability, which may be modified by the genetic architecture of IBD leading to clinical arthropathy.