Presentation of enthesitis-related arthritis and juvenile-onset spondyloarthritis: a cross-sectional study in a pediatric and adult clinic.

BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a whole spectrum of chronic arthritis starting before 16 years of age. The study aims to explore the clinical and demographic descriptors, treatment, and disease progression of enthesitis-related arthritis (ERA) in comparison with juvenile-onset spondyloarthritis (SpA). METHODS: Cross-sectional analysis of consecutive patients in two dedicated clinics, with a single visit and retrospective case-notes review. Arthritis, enthesitis and sacroiliitis were evaluated by scoring disease activity and damage. Continuous variables were reported by median, interquartile range; categorical variables were reported by the frequency comparison of the two groups. RESULTS: Thirty-three cases were included, being 23 (69.7%) with ERA. The median age at diagnosis was 12.5 y (SpA) vs. 9 y (ERA) (p < 0.01); the time from symptom onset to diagnosis was 5.5 y (SpA) vs. 1.5 y (ERA) (p < 0.03). In both groups, the predominant presentation was a single joint or < 5 lower limb joints and asymmetric involvement, with a high frequency of enthesitis. There was a higher frequency of mid-tarsal and ankle synovitis in the ERA group and hip involvement in those with SpA. The comparison of the frequency of spine symptoms at presentation, 30% SpA vs. 21.7% ERA (p = 0.7), was not significant, and radiographic progression to spinal involvement occurred in 43.5% of ERA patients. The median time for spinal progression and age at onset was 2.2 and 12 y for ERA, and 4 and 16.5 y for SpA, respectively. Activity and damage scores were not significantly different between the groups. Treatment comparison resulted in 91.3% of ERA and 100% SpA being treated, predominantly with NSAIDs in both groups, followed by DMARDs and biologics, with a higher frequency of biologics in SpA. CONCLUSION: The main differences were the late diagnoses of SpA, and the hip and spine involvement, with higher frequency of biologic treatment in juvenile-onset SpA compared to ERA.

Extraarticular manifestations of juvenile idiopathic arthritis and their impact on health-related quality of life.

OBJECTIVES: The objective of this study is to investigate extraarticular manifestations (EAMs) in patients with juvenile idiopathic arthritis (JIA) and assess their impact on health-related quality of life (HRQoL) among these patients. METHODS: This cross-sectional analytic study was carried out on 117 patients with JIA. EAMs were identified clinically by history and examination. Sicca symptoms, peripheral neuropathy, enthesitis, and skin lesions were picked up during clinical examination. Pulmonary involvement was evaluated by high-resolution CT chest. Patients were assessed by abdominal ultrasonography to assess the size of liver and spleen. Atlantoaxial subluxation was evaluated by cervical spine x-rays. Patients were evaluated by Pediatric Quality of Life Inventory-4 (PedsQL-4) and PedsQL-3 arthritis module. RESULTS: The median age of patients was 14 years with a median disease duration 4 years, 82.9% were females. Of the studied 117 JIA patients, 85 patients (72.6%) had at least one EAM. Persistent fatigue (51.3%) was the most prevalent EAM, followed by recurrent skin rash (16.2%), enthesitis (15.4%), recurrent fever (13.7%), and uveitis (12%). Patients with EAMs scored significantly lower in physical functioning (p = 0.001), emotional functioning (p < 0.001), social functioning (p = 0.005), and school functioning (p = 0.001). Regarding PedsQL arthritis module, patients with EAM had also significantly lower scores than did patients without EAM on the domains of pain and hurt (p < 0.001), daily activities (p = 0.008), and worry (p = 0.001). RESULTS: EAMs are prevalent among JIA patients and have a negative impact on their HRQoL. So, early identification and treatment are highly recommended. Key Points • A large percentage of JIA patients experienced at least one extraarticular manifestation (EAM). • Persistent fatigue and recurrent skin rash are the most prevalent EAMs in JIA patients. • JIA patients with EAMs have worse scores in almost all domains of HRQoL.

Assessment of enthesopathy in conventional pelvis radiography: Another tool for spondyloarthritis diagnosis beyond sacroiliitis.

INTRODUCTION/OBJECTIVES: Enthesitis is a cardinal feature of spondylarthritis (SpA), and the pelvis is a common site of enthesitis. This study aimed to establish the association between pelvic enthesis involvement on pelvic X-ray and SpA diagnosis through a radiographic enthesis index (REI) and to assess the reliability and accuracy of this REI. MATERIALS AND METHODS: The participants were SpA patients and a control group composed of patients with chronic lumbar pain without SpA. Three blinded observers assessed each pelvic radiography three times. Three zones were used: Zone I (ZI), the iliopubic ramus; Zone II (ZII), the pubic symphysis, and Zone III (ZIII), the ischiopubic ramus. A grading system was created from 0 to 3 [Grade 0, normal; Grade 1, minimal changes (subcortical bone demineralization and/or periosteal wishkering, seen as radiolucency and trabeculation of the cortical bone upon tendon insertion); Grade 2, destructive changes (Grade 1 findings and erosions at the enthesis site); and Grade 3, findings of Grade 2 plus >2 mm whiskering out of the cortical bone) for the REI. The sum of the results of the three zones was called the total REI. For statistical analysis, we used the weighted kappa statistic adjusted for prevalence and bias using Gwet's agreement coefficient. RESULTS: We enrolled 161 patients, 111 of them with SpA (39.6 % with axial SpA and 47.7 % with peripheral SpA) and 50 without SpA. In the SpA group, 36.7 % and 25.7 % had REI Grades 2 and 3 in ZIII, respectively, while only 6 % of the controls had these grades. For ZI, the frequency of Grades 1 to 3 was 42.3 % in the SpA group (8.1 %, 14.4 %, and 19.8 %, respectively), compared to only 2 % in the controls. ZII was unaffected in most of the patients with SpA (82.9 %) and in the controls (98 %). In the control group, Grade 0 was the most common REI grade in all three zones. The agreement was almost perfect for each zone and between the independent readers. The ROC-curve analysis showed that the highest performance areas were the total REI, ZIII, and ZI. Most (75 %) of the SpA patients without sacroiliitis on X-ray were REI-positive. The sensitivity of the REI for SpA diagnosis was 82 %, while the sensitivity of sacroiliitis on X-ray was 38.7 %. CONCLUSIONS: The assessment of pelvic enthesis using the REI on pelvic radiography may be useful for SpA diagnosis. Total REI, ZIII, and ZI had the highest accuracy and almost perfect reliability. The REI is especially helpful in patients without sacroiliitis on imaging.

Hematological indices in psoriatic enthesopathy: relation to clinical and ultrasound evaluation.

BACKGROUND: Enthesopathy is considered a crucial aspect of assessment and outcome in psoriatic arthritis (PsA). Musculoskeletal ultrasound (MSUS) is a critical tool for accurately detecting enthesitis. Recent research focuses on identifying simple biomarkers for detecting and monitoring psoriatic enthesopathy. Red cell distribution width (RDW), mean platelet volume (MPV), and neutrophil/lymphocyte ratio (NLR) are components of a complete blood count (CBC) and are reliable bio-inflammatory markers in various rheumatic diseases. AIM OF WORK: To measure MPV, RDW, and NLR in psoriatic enthesopathy and determine their relationship to disease activity and MSUS findings. PATIENTS AND METHODS: This study focused on 30 people with psoriatic arthritis (PsA) as per CASPAR criteria, along with 20 control subjects. Enthesopathy was evaluated clinically using the Leeds Enthesitis Index (LEI). The modified Disease Activity Index of Psoriatic Arthritis (DAPSA28) was calculated, and RDW, MPV, NLR, CRP, and ESR were measured. Each enthesis in LEI was radiologically assessed using plain radiography and MSUS according to OMERACT definitions. RESULTS: There was a significant relationship between clinical tenderness, the presence of enthesophytes on plain radiography, and MSUS findings at entheses sites (p < 0.001 for each). Psoriatic patients had higher levels of RDW and MPV (p < 0.001 and 0.01, respectively) than controls, with no significant differences in NLR (p = 0.189) between the two groups. RDW and MPV levels were positively correlated with the DAPSA28 score. CONCLUSION: Monitoring PsA disease activity can be improved by considering RDW and MPV as reliable indicators and using them to screen for psoriatic enthesopathy with MSUS indices. Key points • Clinically identifying enthesitis in patients with PsA can be challenging. Imaging MSUS indices hold promise for objective analysis, but there is no consensus on which indices to use in clinical trials and daily practice. • Patients with psoriatic enthesopathy have higher RDW and MPV levels, which are positively correlated with DAPSA28 score. • RDW and MPV can be considered in the turn of improved screening of psoriatic enthesopathy with MSUS scores.

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.

Power Doppler signal at the enthesis and bone erosions are the most discriminative OMERACT ultrasound lesions for SpA: results from the DEUS (Defining Enthesitis on Ultrasound in Spondyloarthritis) multicentre study.

OBJECTIVES: To assess, in spondyloarthritis (SpA), the discriminative value of the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and their associations with clinical features in this population. METHODS: In this multicentre study involving 20 rheumatology centres, clinical and ultrasound examinations of the lower limb large entheses were performed in 413 patients with SpA (axial SpA and psoriatic arthritis) and 282 disease controls (osteoarthritis and fibromyalgia). 'Active enthesitis' was defined as (1) power Doppler (PD) at the enthesis grade ≥1 plus entheseal thickening and/or hypoechoic areas, or (2) PD grade >1 (independent of the presence of entheseal thickening and/or hypoechoic areas). RESULTS: In the univariate analysis, all OMERACT lesions except enthesophytes/calcifications showed a significant association with SpA. PD (OR=8.77, 95% CI 4.40 to 19.20, p<0.001) and bone erosions (OR=4.75, 95% CI 2.43 to 10.10, p<0.001) retained this association in the multivariate analysis. Among the lower limb entheses, only the Achilles tendon was significantly associated with SpA (OR=1.93, 95% CI 1.30 to 2.88, p<0.001) in the multivariate analyses. Active enthesitis showed a significant association with SpA (OR=9.20, 95% CI 4.21 to 23.20, p<0.001), and unlike the individual OMERACT ultrasound lesions it was consistently associated with most clinical measures of SpA disease activity and severity in the regression analyses. CONCLUSIONS: This large multicentre study assessed the value of different ultrasound findings of enthesitis in SpA, identifying the most discriminative ultrasound lesions and entheseal sites for SpA. Ultrasound could differentiate between SpA-related enthesitis and other forms of entheseal pathology (ie, mechanical enthesitis), thus improving the assessment of entheseal involvement in SpA.

Detection of subclinical enthesitis by ultrasonography in patients with psoriasis and controls.

INTRODUCTION: Psoriasis is a widespread chronic inflammatory skin disease; enthesitis is inflammation of the tendon, ligament, and joint capsule insertion, prevalent in patients with psoriatic arthritis. OBJECTIVES: The aim of study to evaluate the utility of the Madrid Sonography Enthesitis Index scoring system for accurate detection of subclinical enthesitis in patients with Psoriasis compared with healthy controls. Another objective was to assess increase in enthesis area and Psoriatic arthritis incidence, in a prospective 1-year follow-up. METHOD: Patients aged ≥18 years who were diagnosed with Psoriasis, without musculoskeletal complaints, and who did not have any clinical sign and/or symptom of enthesitis and synovitis were included in the study. The patients and healthy controls were evaluated with ultrasonography. Ultrasonography evaluation consisted of the detection of gray-scale enthesitis and power Doppler signal in the enthesis areas. The Madrid Sonography Enthesitis Index scoring system was used to quantify the extent of the sonographic enthesis abnormalities. RESULTS: The mean MASEI score, structure, thickness, erosion, and calcification were significantly higher in the Psoriasis group than in the control group. The mean MASEI score, structure, erosion, and calcification measurements were significantly higher at the last examination when compared to the first examination. The triceps was the most commonly affected tendon in both groups. CONCLUSION: Ultrasonography is an important tool for diagnosis and follow-up of subclinical enthesitis in patients with psoriasis. Regardless of disease duration and severity, patients should be screened using ultrasonography at yearly intervals.

DKK-1 in psoriatic arthritis: Correlation with disease activity and enthesopathy.

BACKGROUND: Psoriatic arthritis (PsA) is a complex inflammatory disease with varied clinical characteristics. A pathognomonic characteristic of PsA is enthesitis. Entheseal inflammation ultimately leads to the production of new bone (enthesophytes). Dickkopf-related protein-1 (DKK-1) is a wingless (Wnt) inhibitor that inhibits osteoblast function. OBJECTIVES: Assessment of the serum level of DKK-1 and its association with disease activity and enthesopathy in PsA patients. METHODS: This observational case-control study included 50 PsA patients and 50 healthy volunteers matched for age and gender. All participants were subjected to full medical history, clinical assessment, PSA activity using Disease Activity Index for Psoriatic Arthritis (DAPSA) score, the severity and extent of psoriasis were determined by the Psoriasis Area and Severity Index (PASI). Ultrasonographic assessment of the entheses was done in accordance with the Madrid Sonographic Enthesitis Index (MASEI). Serum level of DKK-1 and correlation with disease activity and enthesopathy in PsA patients were assessed. RESULTS: There was no significant difference between patients and controls regarding age and sex. The mean value of SPARCC index, DAPSA score and PASI score were 6.74±4.58, 33.24±15.26, and 8.35±10.93, respectively. There was significant difference between patients and controls regarding the serum levels of DKK-1 and MASEI score (p<0.0001). There was a significant positive correlation between serum DKK-1 and MASEI (r: 0.43527, p: 0.00158), MASEI inflammatory (r: 0.37958, p: 0.00655), and MASEI damage (r: 0.38384, p: 0.00593). CONCLUSIONS: Serum DKK-1 levels were elevated in PsA patients and were found to be correlated with MASEI score for enthesopathy.

'Double target' ultrasound monitoring of biologic therapy in psoriatic arthritis.

OBJECTIVES: We aimed to 1) evaluate by power Doppler (PD) ultrasound (US) the response to therapy of the most inflamed joint and enthesis (target sites) in psoriatic arthritis (PsA) patients starting a biologic disease-modifying anti-rheumatic drug (bDMARD); and 2) to investigate the correlation between the US response and clinical data. METHODS: Consecutive PsA patients with US synovitis and US 'active' enthesitis, starting a bDMARD, were included. The joint with the highest OMERACT-EULAR-US composite score and the enthesis with the highest PD grade (targets) were identified at baseline. The US examination and clinical assessment were performed at 0, 3 and 6 months. The response of OMERACT-EULAR-US synovitis composite score was defined as reaching a grade = 0 at follow-up examination; synovial and entheseal PD responses were defined as a PD=0 and/or a reduction of ≥2 PD grades at follow-up examination. RESULTS: Thirty patients were included. Synovitis composite score, synovial PD and entheseal PD showed significant responses at 3 and 6 months compared to baseline (p<0.01). Synovial PD responses were higher than entheseal PD responses at 3 months (71.4% vs 40.0%, p=0.01) and 6 months (77.8% vs. 46.7%, p=0.02). US synovitis responses were correlated with DAPSA (p<0.01) and MDA responses (p=0.01 for composite score, p=0.02 for PD). CONCLUSIONS: US was found sensitive for monitoring treatment response in PsA patients starting a biologic drug. Entheseal PD was less responsive than synovial PD, suggesting that enthesitis may represent a 'difficult-to-treat' domain in PsA.

Subclinical enthesitis in enthesitis-related arthritis and sacroiliitis associated with familial Mediterranean fever.

OBJECTIVES: In our study, we investigated the presence of subclinical enthesitis by ultrasonography (US) in asymptomatic patients with enthesitis-related arthritis (ERA) and sacroiliitis associated with familial Mediterranean fever (FMF). METHODS: A total of 50 patients, including 35 patients with ERA and 15 with sacroiliitis associated with FMF, were included in the study. All patients were evaluated with US by a paediatric radiologist. Enthesis of seven tendons (common extensor and flexor tendons, quadriceps tendon, proximal and distal patellar tendon, Achilles tendon, and plantar fascia) was examined on both sides. RESULTS: Subclinical enthesitis was detected in 10 ERA (28.5%) and three FMF (20%) patients. Enthesitis was radiologically diagnosed in 16 (2.3%) out of 700 evaluated entheseal sites. The most frequent sites of enthesitis were Achilles (37.5%) and quadriceps (31.3%) tendons. All patients were in clinical remission and had no active complaints, and acute phase reactants were within normal limits. Therefore, the patients were followed up without treatment change. However, disease flare-up was observed in three of these patients (23.1%) during the follow-up, and their treatments were intensified. CONCLUSIONS: Our results showed that the US can be particularly helpful in detecting subclinical enthesitis and predicting disease flare-ups.

The association between sonographic enthesitis with sonographic synovitis and tenosynovitis in psoriatic arthritis patients.

OBJECTIVES: To examine the association between sonographic enthesitis with sonographic synovitis and tenosynovitis in PsA patients, and the association between sonographic enthesitis and clinical characteristics. METHODS: Consecutive PsA patients that fulfilled the ClASsification criteria for Psoriatic ARthritis (CASPAR) were prospectively recruited. Each patient was evaluated by comprehensive clinical and sonographic assessment (greyscale and Doppler), the latter including 52 joints, 40 tendons and 14 entheses [according to MAdrid Sonography Enthesitis Index (MASEI) plus lateral epicondyles] performed by an experienced sonographer blinded to the clinical data. The US enthesitis score was further categorized to inflammatory (hypoechogenicity, thickening, bursitis and Doppler) and structural (enthesophytes/calcifications and erosions) subcategories. Multivariate linear regression models assessed the association between enthesitis and the selected variables. RESULTS: A total of 158 PsA patients [mean (s.d.) age 52.3 (13) years, 88 (55.7%) females] were analysed. Multivariate linear regression analyses showed a significant association between sonographic enthesitis and sonographic synovitis (ß = 0.18, P = 0.008) and between sonographic enthesitis and sonographic tenosynovitis (ß = 0.06, P = 0.02). These associations were derived from the enthesitis inflammatory subcategory of the MASEI (P < 0.05). Associations between enthesitis and synovitis were also demonstrated on the level of the elbow, knee and ankle joints (P < 0.05). In addition, sonographic enthesitis was significantly associated with older age, male sex, swollen joint count, CRP level and physical occupation. CONCLUSIONS: Sonographic enthesitis is associated with sonographic synovitis and tenosynovitis. The severity of sonographic enthesitis may represent a marker for inflammatory activity in other musculoskeletal domains.

The burden of entheseal involvement in systemic lupus erythematosus: a comparative ultrasonograghic study.

BACKGROUND: Imaging is crucial for identifying and diagnosis of the musculoskeletal (MSK) symptoms, which are one of the most typical manifestations of systemic lupus erythematosus (SLE). For the joints, tendons, and entheseal sites, ultrasonography has shown to be sensitive and accurate for the diagnosis of both inflammation and structural damage. AIM: The goal of the current investigation is to determine the prevalence and the distribution of entheseal abnormalities in SLE patients, using musculoskeletal ultrasonography (MSUS) and to assess the relationship between entheseal sonographic changes and the SLE disease activity. PATIENTS AND METHODS: One hundred sixty-eight subjects were studied (56 SLE patients, 56 psoriatic arthritis (PSA) patients, and 56 normal cases). To compare the frequency and the distribution of entheseal involvement, high-resolution MSUS was conducted to assess the entheseal sites of all patients in accordance with the Madrid Sonographic Enthesitis Index (MASEI). RESULTS: Clinical enthesitis was detected in 39.3% of the SLE patients using the Leeds Enthesitis Index compared to 71% detected via US examination, indicating a high proportion of subclinical enthesitis in our SLE patients. The most frequently affected enthesis was the distal insertion of the patellar tendon at the tibial tuberosity which was detected in 41% of SLE patients. Enthesitis was significantly more frequent in PSA patients (100%) compared to SLE patients (71.4%) (p < 0.05) and more significantly frequent in SLE patients compared to the healthy controls (19.6%). There was a significant correlation between MASI and SLEDAI scores (r = 0.250*, p = 0.048) and the total protein in 24 h (r = 0.289*, p = 0.031). In addition, there was an inverse significant correlation between MASEI and serum albumin (r = - 0.324*, p = 0.015). CONCLUSION: In SLE patients, enthesitis is frequently clinical and ultrasound-verified. The most impacted enthesis is at the insertion of the quadriceps tendon. Enthesitis presence and the rise in the MASI score can serve as indicators of the severity of the SLE disease. Key Points • The most impacted entheseal site lies at the insertion of the quadriceps tendon. • The presence and the rise in MASEI score can serve as indicators of the severity of the SLE disease.

Demonstrating the relationship of ultrasonographic parameters with disease activity and pain in lateral epicondylitis.

To evaluate the relationship of ultrasonographic evaluation parameters with pain, muscle strength and disease severity in lateral epicondylitis (LE). 64 people were included in present retrospective, cross-sectional study. Activity and rest pain was questioned with Visual Analog Scale (VAS). Also, Patient Rated Tennis Elbow Evaluation (PRTEE) and the maximum grip strength were evaluated. Hypoechoic region, neovascularity, cortical irregularity, enthesopathy and peritendinous fluid or bursitis were evaluated by ultrasonography. 48 of the patients were female and 16 were male. Mean age was 48.53 ±â€…6.12, body mass index was 27.70 ±â€…4.75. 55 (85.9%) hypoechoic region, 31 (48.4%) neovascularity, 21 (32.8%) cortical irregularity, 19 (29,7%) enthesopathy, and 18 (28.1%) peritendinous fluid or bursitis were detected by ultrasonography. When the ultrasonographic findings and clinical findings of the patients were compared, no significant difference was found between the hypoechoic region, cortical irregularity, enthesopathy and clinical findings (P > .05), while the extension grip strength was found to be significantly lower in patients with neovascularity (P = .045). In addition, patients with peritendinous fluid or bursitis, were found to be significantly lower in both flexion (P = .033) and extension (P = .023) grip strength, while PRTEE function (P = .021) subgroup and total (P = .038) scores were significantly higher. Hypoechoic region, cortical irregularities and enthesopathy were not evaluated to be associated with disease severity, pain and muscle strength. Neovascularity was found to be associated only with extension grip strength. Peritendinous fluid or bursitis was found to be associated with both flexion and extension grip strength and disease activity, but not associated with pain.

Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension.

OBJECTIVES: In the ULTIMATE study with an open label extension, we assessed the long-term effect of secukinumab at tissue level on synovitis and enthesitis, and across all psoriatic arthritis (PsA) manifestations, using both clinical evaluations and power Doppler ultrasonography (PDUS). METHODS: This randomised, placebo-controlled, Phase 3 study (ULTIMATE) included biologic-naïve patients with PsA with active PDUS synovitis and clinical enthesitis, and inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The study consisted of 3 treatment periods; in the first period (baseline to week 12) patients were randomised to receive subcutaneous secukinumab (150 mg or 300 mg according to severity of skin psoriasis) or placebo every week until week 4 and once every 4 weeks up to week 12. In the second period (weeks 12-24) all patients received open-label secukinumab with placebo patients switching to secukinumab (150 mg or 300 mg). The third period (weeks 24-52) was an extended open-label treatment period. The long-term responsiveness of the Global EULAR-OMERACT Synovitis Score (GLOESS), clinical enthesitis and global PDUS-detected enthesitis score (using two candidate definitions of activity) at patient level, together with clinical efficacy across key manifestations of PsA and safety were assessed. RESULTS: Of the 166 patients enrolled, 144 completed week 52. A significant reduction in GLOESS was demonstrated in the secukinumab group vs placebo at week 12, followed by a stable reduction of synovitis until week 52 in the secukinumab group while placebo switchers from week 12 reached a similar level of reduction at week 24 with stability thereafter. Likewise, a significant reduction in the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was shown in the secukinumab group vs placebo at week 12 with sustained improvement to week 52. Global OMERACT PDUS enthesitis scores were numerically lower in secukinumab vs placebo switchers in the first two treatment periods, with some stability in the third period in both groups. Improvements in clinical responses were also observed across all key domains of PsA up to week 52 in both treatment groups with no new or unexpected safety signals. CONCLUSIONS: ULTIMATE showed consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis and sustained clinical efficacy through week 52 in patients with PsA treated with secukinumab and placebo switched to secukinumab.

Advances in the Evaluation of Peripheral Enthesitis by Magnetic Resonance Imaging in Patients With Psoriatic Arthritis.

Enthesitis is a key disease manifestation in patients with psoriatic arthritis (PsA) that considerably contributes to pain, lower physical function, and reduced quality of life. Clinical assessment of enthesitis lacks sensitivity and specificity, and therefore better methods are urgently needed. Magnetic resonance imaging (MRI) allows detailed assessment of the components of enthesitis, and consensus-based validated MRI scoring systems exist. These include the Outcome Measures in Rheumatology (OMERACT) Heel Enthesitis MRI Scoring System (HEMRIS) method, which assesses the entheses of the heel region in a detailed manner, and the OMERACT MRI Whole-Body Score for Inflammation in Peripheral Joints and Entheses (MRI-WIPE) method, which provides an overall assessment of the inflammatory burden in the peripheral entheses and joints in the entire body using whole-body MRI. At an MRI workshop at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2022 meeting in Brooklyn, the MRI appearances of peripheral enthesitis were described, as were the scoring methods. The utility of MRI for improved assessment of enthesitis was demonstrated with examples of patient cases. Clinical trials in PsA that evaluate enthesitis by MRI as a key endpoint should include the presence of MRI enthesitis as an inclusion criterion, and apply validated MRI outcomes to assess the effect of therapeutics on enthesitis are recommended.

Mineral tessellation in mouse enthesis fibrocartilage, Achilles tendon, and Hyp calcifying enthesopathy: A shared 3D mineralization pattern.

The hallmark of enthesis architecture is the 3D compositional and structural gradient encompassing four tissue zones - tendon/ligament, uncalcified fibrocartilage, calcified fibrocartilage and bone. This functional gradient accommodates the large stiffness differential between calcified bone and uncalcified tendon/ligament. Here we analyze in 3D the organization of the mouse Achilles enthesis and mineralizing Achilles tendon in comparison to lamellar bone. We use correlative, multiscale high-resolution volume imaging methods including µCT with submicrometer resolution and FIB-SEM tomography (both with deep learning-based image segmentation), and TEM and SEM imaging, to describe ultrastructural features of physiologic, age-related and aberrant mineral patterning. We applied these approaches to murine wildtype (WT) Achilles enthesis tissues to describe in normal calcifying fibrocartilage a crossfibrillar mineral tessellation pattern similar to that observed in lamellar bone, but with greater variance in mineral tesselle morphology and size. We also examined Achilles enthesis structure in Hyp mice, a murine model for the inherited osteomalacic disease X-linked hypophosphatemia (XLH) with calcifying enthesopathy. In Achilles enthesis fibrocartilage of Hyp mice, we show defective crossfibrillar mineral tessellation similar to that which occurs in Hyp lamellar bone. At the cellular level in fibrocartilage, unlike in bone where enlarged osteocyte mineral lacunae are found as peri-osteocytic lesions, mineral lacunar volumes for fibrochondrocytes did not differ between WT and Hyp mice. While both WT and Hyp aged mice demonstrate Achilles tendon midsubstance ectopic mineralization, a consistently defective mineralization pattern was observed in Hyp mice. Strong immunostaining for osteopontin was observed at all mineralization sites examined in both WT and Hyp mice. Taken together, this new 3D ultrastructural information describes details of common mineralization trajectories for enthesis, tendon and bone, which in Hyp/XLH are defective.

The use of ultrasound to detect enthesitis as a potential guide for intervention in patients with psoriasis at risk of psoriatic arthritis: a systematic review.

INTRODUCTION: Psoriatic arthritis is estimated to develop in 2% of patients with psoriasis per year and can result in significant morbidity. Early diagnosis and treatment of psoriatic arthritis are imperative to prevent irreversible arthritic joint damage. Dermatologists play a key role in identifying patients who are at risk for or with early signs of psoriatic arthritis. Subclinical enthesopathy may be a risk factor for psoriatic arthritis or an early sign of the disease and can be detected using ultrasound. METHODS: In this systematic review, we determined the prevalence of ultrasound-diagnosed enthesitis in psoriasis patients, as well as their risk of subsequent progression to psoriatic arthritis. RESULTS: We determined that the detection of enthesitis on ultrasound was associated with higher risk of future psoriatic arthritis. Systemic therapy was associated with improvement in enthesitis findings in patients with psoriasis but not in those with chronic structural damage or established psoriatic arthritis. Additionally, one study showed that ustekinumab treatment resulted in a significantly lower rate of psoriatic arthritis development. CONCLUSIONS: These studies support the value of early detection and treatment in the prevention of progression to psoriatic arthritis, as well as the use of ultrasound for screening for risk factors in psoriasis patients. Future studies are needed to further evaluate when preventative therapy can be useful among patients with psoriasis with risk factors for psoriatic arthritis.

Prevalence and clinical associations of ultrasound-confirmed enthesitis in systemic lupus erythematosus.

OBJECTIVES: To assess the prevalence of US-confirmed enthesitis in a cohort of patients with SLE and to analyse the clinical associations to enthesitis during the course of SLE. METHODS: In a retrospective analysis of the SLE cohort of the Lupus Unit of the Careggi University Hospital, US examinations of SLE patients presenting with tender and/or swollen joints were retrieved to assess the presence of enthesitis. Patients with US-proven enthesitis were compared with SLE controls with tender and/or swollen joints who showed no US evidence of enthesitis. Clinical and laboratory features were compared at disease onset and during follow-up. RESULTS: A total of 400 patients fulfilling EULAR/ACR classification criteria for SLE were assessed. Of these, 106 underwent articular US examination. Evidence of enthesitis was found in 31/106 (29.2%) patients. Seventy-one patients without US-enthesitis were included as controls; four were excluded due to lack of follow-up data. Laboratory and clinical features were comparable between cases and controls at disease onset. Throughout a median follow-up of 10.0 (interquartile range [IQR] 8.3-23.3) years for cases and 12.4 (IQR 7.2-13.3) years for controls, patients with enthesitis were less likely to develop renal involvement (22.6% vs 46.5%, P = 0.028) and failed B cell depletion more frequently (75.0% vs 0%). CONCLUSION: In SLE patients with clinically active joints, US-proven enthesitis is a fairly common finding. Enthesitis in SLE could be the hallmark of a distinct disease phenotype with less renal involvement, more arthritis and low response to anti-CD 20 therapy, potentially requiring a tailored treatment.