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To examine whether treatment with interleukin (IL)-1-, IL-6-, tumour necrosis factor α (TNFα)-inhibitors or Abatacept is associated with an increased risk of common infections, infections requiring hospitalization (SAE) or opportunistic infections among real-world juvenile idiopathic arthritis (JIA) patients. Furthermore, the influence of other patient-related covariates on the occurrence of infections was investigated. Patients diagnosed with JIA and treated with biologics were selected from the German BIKER registry. Incidence rates (IR) of infections per 100 person years were calculated and compared between the different cohorts. Using multivariate logistic regression, odds ratios with 95% confidence intervals (CI) were determined for the influence of patient-related covariates (age, diagnosis, laboratory data, concomitant medication, JIA activity, comorbidities, and premedication) on the occurrence of infections. 3258 patients entered the analysis. A total of 3654 treatment episodes were distributed among TNFα- (Etanercept, Adalimumab, Golimumab, Infliximab, n = 3044), IL-1- (Anakinra, Canakinumab, n = 105), IL-6- (Tocilizumab, n = 400) and T-cell activation inhibitors (Abatacept, n = 105). 813 (22.2%) patients had at least one infection, 103 (2.8%) patients suffered from an SAE infection. Both common and SAE infections were significantly more frequent in IL-1 (IR 17.3, 95% CI 12.5/24 and IR 4.3, 95% CI 2.3/8.3) and IL-6 cohort (IR 16.7, 95% CI 13.9/20 and IR 2.8, 95% CI 1.8/4.4) compared to TNFα-inhibitor cohort (IR 8.7, 95% CI 8.1/9.4 and IR 1, 95% CI 0.8/1.3). When comparing the influencing factors for various infectious diseases, the use of corticosteroids, younger age, cardiac comorbidities and higher JIA-activity are the most striking risk factors. Relative to TNFα inhibitors and Abatacept, IL-1 and IL-6 inhibitors were associated with an increased risk of common and SAE infections. The influencing covariates identified may be helpful for the choice of a suitable biologic to treat JIA.

In unserem Artikel werden aktuelle Bedeutung und Entwicklung der Gelenksonografie als fester Bestandteil eines „Treat-to-Target“-Konzeptes bei der Behandlung der juvenilen idiopathischen Arthritis (JIA) dargestellt und diskutiert. Dabei nimmt die Gelenksonografie neben der klinischen Untersuchung eine entscheidende Rolle in der fruhen Diagnosestellung einer JIA ein mit dem Ziel, dem Patienten so fruh wie moglich eine effiziente Therapie zukommen zu lassen (Window of Opportunity). Zusatzlich kann die Gelenksonografie, eingebettet in das „Treat-to-Target“-Konzept, eine wichtige Rolle in der Verlaufskontrolle und Evaluation einer subklinischen Entzundungsaktivitat spielen. Bisherige etablierte Diagnose-, Verlaufs- und auch Remissionskriterien einer JIA lassen stringente und objektivierbare bildgebende Kriterien vermissen, obwohl sich Qualitat und Erfahrung bei der Gelenksonografie stetig verbessern. Neben den sonografischen Kriterien haben sich inzwischen auch verschiedene Biomarker zur Beurteilung der Krankheitsaktivitat etabliert. Mit der Entwicklung der Sonografie und sicheren Testung von Biomarkern konnte sich in Zukunft zur fruhen Diagnosestellung und sicheren Remissionseinschatzung eine Kombination aus immunologischen und sonografischen Kriterien etablieren, die das bisherige „Treat-to-Target“-Konzept bei der JIA unterstutzen und verbessern. In this article the current role and development of musculoskeletal ultrasound as a central component of treat-to-target management of JIA is discussed. Musculoskeletal ultrasound alongside clinical examination plays a significant role in the early diagnosis of JIA, with the aim of initiating treatment as soon as possible and within the “window of opportunity”. Including ultrasound in treat-to-target strategies could play an important role in the monitoring and evaluation of clinical as well as subclinical inflammation. However, despite continuous improvements in the quality and experience of ultrasound capabilities, existing diagnostic, prognostic and remission criteria are still lacking objective imaging-specific criteria. Other than ultrasound, immunological biomarkers have also shown utility for the evaluation of clinical activity. The development of ultrasound and routine testing of biomarkers, and potentially both combined, could allow earlier diagnosis and more accurate prediction of disease remission, thereby supporting and improving the ability to treat JIA to target.

This article reviews the role of musculoskeletal ultrasound (MSUS) for the diagnosis, monitoring and treat-to-target management of JIA. Technological advancements in MSUS allow more precise evaluation of arthritis, tenosynovitis and enthesitis versus clinical examination alone, which may assist treatment decisions. In adult studies, serum and synovial biomarkers have correlated with MSUS findings. Within paediatric rheumatology, significant developments in the definition of normal and pathology, a necessity for the future integration of MSUS into treat-to-target management, have already been reached or are underway, which in turn could allow tighter control of disease activity and earlier identification of treatment response and failure, bringing the goal of ‘precision medicine’ closer. Additionally, the utility of MSUS for the evaluation of subclinical disease remains an unexamined area of interest. ‘Ultrasound remission’ combined with clinical assessment and immunological markers could therefore potentially improve the treat-to-target management of JIA.

Objectives To determine (i) correlates for etanercept (ETA) discontinuation after achieving an inactive disease and for the subsequent risk of flare and (ii) to analyze the effectiveness of ETA in the re-treatment after a disease flare. Methods Data from two ongoing prospective registries, BiKeR and JuMBO, were used for the analysis. Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in juvenile idiopathic arthritis (JIA) patients treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs) and conventional synthetic DMARDs (csDMARDs). Results A total of 1724 patients were treated first with ETA treatment course (338 with second, 54 with third ETA course). Similar rates of discontinuation due to ineffectiveness and adverse events could be observed for the first (19.4%/6.2%), second (18.6%/5.9%), and third (14.8%/5.6%) ETA course. A total of 332 patients (+/−methotrexate, 19.3%) discontinued ETA after achieving remission with the first ETA course. Younger age (hazard ratio (HR) 1.08, p p = 0.004), and shorter duration between JIA onset and ETA start (HR 1.10, p p n = 117 of 161; 72.7%) after the flare. One in five patients (n = 23, 19.7%) discontinued ETA again after achieving an inactive disease and about 70% of the patients achieved an inactive disease 12 months after restarting ETA. Conclusion The study confirms the effectiveness of ETA even for re-treatment of patients with JIA. Our data highlight the association of an early bDMARD treatment with a higher rate of inactive disease indicating a window of opportunity.

Pediatric rheumatology 19(1), 38 (2021). doi:10.1186/s12969-021-00510-8, Published by BioMed Central, London

Background Defining of gray scale ultrasound standard reference values of the shoulder joint in childhood and adolescence during maturation. Patients: We examined 445 healthy girls and boys between 1 year and 18 years of age. Method A cross-sectional multicentre grey-scale ultrasound study was performed to examine the shoulder joint on both sides. The children were divided according to their gender and were further classified into six age groups, which constituted three-year age ranges, to record anatomical development changes. We measured the capsule-bone distance (BCD) as a representation of the intracapsular cavity, as well as the thickness of the joint capsule and joint cartilage. Values were expressed in mean±standard deviation (SD) and minimum-maximum (min-max). The shape of the joint capsule and capsule-bone junction zone was qualitatively analysed. Results The joint cartilage thickness decreased with increasing age in all joints independently from sex and body side. However, the BCD and the capsule thickness increased with age. There was no intraarticular fluid visible. The joint capsule had a predominantly concave form, whereas the capsule-bone junction was mostly sharp. Discussion This study is the first describing age-related normal values of the intracapsular cavity, joint capsule and cartilage thickness as well as their respective shape in a large cohort of healthy children. Conclusion The findings could be helpful to differentiate between physiological and pathological joint conditions and thereby distinguishing age-related variations from alterations caused by inflammation.

Objective To determine the intra- and inter-observer reliability of ultrasound (US)-detected age-related joint vascularization and ossification grading in healthy children. Methods Following standardized image acquisition and machine setting protocols, 10 international US experts examined four joints (wrist, second metacarpophalangeal joint, knee, and ankle) in 12 healthy children (divided into four age groups: 2–4, 5–8, 9–12, and 13–16 years). Grey-scale was used to detect the ossification grade, and power Doppler (PD) US was used to detect physiological vascularization. Ossification was graded from grade 0 (no ossification) to grade 3 (complete ossification). A positive PD signal was defined as any PD signal inside the joint. Kappa statistics were applied for intra- and inter-observer reliability. Results According to the specific joint and age, up to four solitary PD signals (mean, 1.5) were detected within each joint area with predominant localization of the physiological vascularization in specific anatomic positions: fat pad, epiphysis, physis, and short bone cartilage. The kappa values for ossification grading were 0.87 (range, 0.85–0.91) and 0.58 for intra- and inter-observer reliability, respectively. The bias-adjusted kappa values for intra- and inter-observer reliability were 0.71 (range, 0.44–1.00) and 0.69, respectively. Conclusion Detection of normal findings (i.e., grading of physiological ossification during skeletal maturation and identification of physiological vessels) can be highly reliable by using clear definitions and a standardized acquisition protocol. These data will permit development of a reliable and standardized US approach for evaluating paediatric joint pathologies. This article is protected by copyright. All rights reserved.

The role of ultrasound imaging in the diagnosis and monitoring of paediatric rheumatic diseases with special emphasis on recent scientific work regarding the evidence base and standardization of this technique is being reviewed. An overview of the most important practical aspects for the use of musculoskeletal ultrasound in a clinical setting is also provided. Huge scientific efforts and advances in recent years illustrate the increasing importance of musculoskeletal ultrasound in pediatric rheumatology. Several studies focused on setting an evidence-based standard for the ultrasound appearance of healthy and normal joints in children of all age groups. Physiologic vascularization and ossification were two main aspects of these studies. Other publications demonstrate that ultrasound imaging is also an important and useful tool to detect pathology as synovitis, tenosynovitis or enthesitis in children and to monitor pediatric patients with rheumatic conditions. Important practical aspects include training in the use of correct ultrasound techniques, as well as knowledge and experience of normal pediatric sonoanatomy and the appearance of pathological findings on ultrasound.

The Second author’s name was incorrectly published in the original article. The correct name is Hartwig Wilhelm Lehmann.

Objective. Musculoskeletal (MS) ultrasound (US) is increasingly being used as an extension of paediatric clinical practice, particularly in the clinical management of children with juvenile idiopathic arthritis (JIA). MSUS is most commonly used in the assessment of effusion and synovial hypertrophy and detection of soft tissue disorders. It can also be used to visualise other structures, such as hyaline cartilage and bone surfaces. Given the unique anatomy of the growing skeleton, many of the difficulties encountered in its use result from misinterpretation of MSUS images. Thus, a detailed knowledge of anatomy in healthy children, both in B-mode and Doppler mode, is mandatory. Additionally, as US is the most operator-dependent imaging modality, the experience and expertise of the examiner will determine the value of the diagnostic information obtained from this technique. Incorrect acquisition and interpretation of images may result in inappropriate disease management. Thus, a systematic scanning method and a standardised evaluation procedure are essential in children.

Objectives To develop and test the reliability of a new semiquantitative scoring system for the assessment of cartilage changes by ultrasound in a web-based exercise as well as a patient exercise of patients with RA. Methods A taskforce of the Outcome Measures in Rheumatology Ultrasound Working Group performed a systematic literature review on the US assessment of cartilage in RA, followed by a Delphi survey on cartilage changes and a new semiquantitative US scoring system, and finally a web-based exercise as well as a patient exercise. For the web-based exercise, taskforce members scored a dataset of anonymized static images of MCP joints in RA patients and healthy controls, which also contained duplicate images. Subsequently, 12 taskforce members used the same US to score cartilage in MCP and proximal interphalangeal joints of six patients with RA in in a patient reliability exercise. Percentage agreement and prevalence of lesions were calculated, as intrareader reliability was assessed by weighted kappa and interreader reliability by Light’s kappa. Results The three-grade semiquantitative scoring system demonstrated excellent intrareader reliability (kappa: 0.87 and 0.83) in the web-based exercise and the patient exercise, respectively. Interreader reliability was good in the web-based exercise (kappa: 0.64) and moderate (kappa: 0.48) in the patient exercise. Conclusion Our study demonstrates that ultrasound is a reliable tool for evaluating cartilage changes in the MCP joints of patients with RA and supports further development of a new reliable semiquantitative ultrasound scoring system for evaluating cartilage involvement in RA.

Due to maturation of joints, various changes take place, not only in the field of paediatric rheumatology but also in paediatric orthopaedics musculoskeletal ultrasound plays an important role in both the diagnosis and the follow-up of diseases in this field. To differentiate between physiological and pathological findings, the knowledge of reference values of joint structures is indispensable. The objective was to define B-mode ultrasound age- and sex-related reference values for the elbow joint in healthy children and adolescents during maturation. In a cross-sectional, multicentre ultrasound study we examined both sides of the elbow joints of 437 healthy children and adolescents (194 boys/243 girls) being between one and less than 18 years old. The children were classified into six equal age groups and divided according to their gender. We measured the distance between the outer margin of the joint capsule and the bone surface to define the bone-capsule distance (BCD), the thickness of the joint cartilage as well as the thickness of the joint capsule. The bone–capsule junction zone and the shape of the joint capsule were analysed qualitatively. The bone capsule distance and the capsule thickness increased with age. In contrast, the joint cartilage thickness decreased. In most cases the junction zone was peaked. The joint capsule showed mostly a concave shape. Intra- and interobserver reliabilities were good. We propose B-mode ultrasound age- and sex-related reference values for the elbow joint in a large number of healthy children and adolescents for the first time. By applying these standard values to the ultrasound examination of the elbow joint, it may be possible to achieve greater certainty in the diagnosis of pathological processes.

Objectives Musculoskeletal ultrasonography (US) has the potential to be an important tool in the assessment of disease activity in childhood arthritides. To assess pathology, clear definitions for synovitis need to be developed first. The aim of this study was to develop and validate these definitions through an international consensus process. Methods The decision on which US techniques to use, the components to be included in the definitions as well as the final wording were developed by 31 ultrasound experts in a consensus process. A Likert scale of 1-5 with 1 indicating complete disagreement and 5 complete agreement was used. A minimum of 80% of the experts scoring 4 or 5 was required for final approval. The definitions were then validated on 120 standardized US images of the wrist, MCP and tibiotalar joints displaying various degrees of synovitis at various ages. Results B-Mode and Doppler should be used for assessing synovitis in children. A US definition of the various components (i.e. synovial hypertrophy, effusion and Doppler signal within the synovium) was developed. The definition was validated on still images with a median of 89% (range 80-100) of participants scoring it as 4 or 5 on a Likert scale. Conclusions US definitions of synovitis and its elementary components covering the entire pediatric age range were successfully developed through a Delphi process and validated in a web-based still images exercise. These results provide the basis for the standardized US assessment of synovitis in clinical practice and research. This article is protected by copyright. All rights reserved.

Background Ultrasound (US) was found to have face and content validity for detecting synovitis in juvenile idiopathic arthritis (JIA) with higher sensitivity than clinical examination. In order to test validity and improve the applicability of US in JIA, the OMERACT US pediatric subtask force recently published preliminary definitions for the sonographic features of synovitis in children. Objectives Aim of this study was to confirm and improve B-mode and color power/Doppler (PD) US definitions for synovial components and grading in children, by using an image and patient based exercise. Methods The definitions were confirmed and modified in a multi-step process. In the 1st step, definitions were developed in multi-round Delphi web based consensus process were ≥80% of participants would need to reach ≥80% of agreement on a Likert scale from 1–5 (1 strongly disagree, 2 disagree, 3 neutral, 4 agree, 5 strongly agree). In the 2nd step, in a face to face meeting, a subgroup of these experts revised the definitions for final wording and performed intra- and inter-observer reliability exercise study in JIA patients as the final 3rd phase of the process. The definitions were tested in four joints (wrist, 2nd MCP, knee and ankle) of JIA patients divided in four age groups following standardized image acquisition and machine setting protocol. Statistics program R (version 3.3.0) was used for the statistical analyses. For intra-rater agreement Cohen kappa and for inter-rater agreement prevalence and bias adjusted kappa (PABAK) were calculated if needed. Results Reliability exercise included 20 JIA patients (distributed in equal numbers by age groups), 14 observers, 4 joints/observer, 3 observers/joint, 360 intra- and 360 inter-observer tests. A 0–3 semi-quantitative B-mode and color power/Doppler US definitions for synovial components and grading, were agreed (presented in Figure 1). Conclusions The proposed synovitis grading for children showed to be reliable why the next step should be to test sensitivity to change in order to possibly be used as an outcome tool in JIA. Disclosure of Interest None declared

OBJECTIVES This study aimed to evaluate normal blood flow in the vertebral arteries and the basilar artery of preterm and term neonates by Doppler sonography. METHODS Blood flow in both vertebral arteries and the basilar artery was examined in 102 neonates between the biological ages of 28 and 41 weeks. Fifty-one boys and 51 girls underwent Doppler sonography. Measurements were usually undertaken at 6 days old. Systolic and diastolic flow velocities, including the resistive index, were measured and analyzed, taking into consideration biological age, weight, and sex. Anatomic aberrations of the vertebral arteries were recorded. RESULTS Mean blood flow values ± SD in the basilar artery were 35.2 ± 7.4 cm/s (systolic velocity) and 10.9 ± 3.5 cm/s (diastolic velocity). Mean blood flow values in the right vertebral artery were 26.8 ± 9.3 cm/s (systolic velocity) and 8.0 ± 3.7 cm/s (diastolic velocity). Mean blood flow values in the left vertebral artery were 28.6 ± 8.3 cm/s (systolic velocity) and 8.7 ± 3.3 cm/s (diastolic velocity). Systolic and diastolic blood flow in both vertebral arteries was significantly higher from 38 to 41 weeks compared with 28 to 32 and 33 to 37 weeks (P < .05). Regression analysis of systolic and diastolic blood flow velocities in the vertebral arteries versus biological age yielded significant results (P < .05). CONCLUSIONS Sonography is an excellent tool for examining blood flow in the basilar and vertebral arteries of premature and term neonates. Mean systolic and diastolic blood flow velocities in the vertebral arteries increase significantly with age.

We evaluated postnatal skeletal development of the proximal femoral epiphysis, distal femoral epiphysis (DFE) and proximal tibial epiphysis (PTE) in 178 premature and mature newborns, between 25 and 47 wk of biological age, using high-resolution B-mode musculoskeletal ultrasound. Approximate age-related values were determined based on the ossification center size and epiphyseal cartilage thickness. The earliest onsets of visible mineralization were at 30 wk of maturity in the DFE, 31 wk in the PTE and 43 wk in the proximal femoral epiphysis. In preterm and term neonates, significant correlations were observed for transverse and longitudinal length of the DFE and PTE with biological age (R² = 0.35-0.50, p

Objectives To produce ultrasound (US) consensus-based definitions of cartilage change in rheumatoid arthritis (RA) and assess its intraobserver and interobserver reliability in a web-based exercise. Methods We conducted a Delphi study on US defined cartilage change and a proposed semiquantitative (SQ) US scoring system for cartilage change in RA. A written Delphi questionnaire was developed based on a systematic literature review and expert international consensus and was distributed via consecutive written questionnaires by email to a group 35 rheumatologists from 17 countries with experience in musculoskeletal US. Taskforce members performed US B mode examination of the metacarpal cartilage in metacarpophalangeal joints 2–5 in RA patients and the images were collected in an electronic database. A reference image atlas of cartilage changes was developed for scoring 123 anonymized images including 25 duplicate images. These were sent to the participants who independently scored the images. Intraobserver reliability was assessed by Cohen9s kappa and interobserver reliability by Fleiss9 kappa. Results Group agreement (76–100%) was reached for 6 statements concerning: i) MSUS definition and assessment of normal hyaline cartilage, ii) elementary cartilage lesions in MSUS and iii) grading of elementary cartilage lesions in patients with RA in a two-round Delphi consensus process. A three-grade SQ (0–2) scoring system (grade 0, normal cartilage; grade 1, minimal change: blurring of outer and/or subchondral margin, focal thinning or incomplete loss of homogeneity of echostructure; grade 2, severe: diffuse thinning or complete loss of homogeneity of echostructure) was agreed for scoring cartilage damage in RA. Both intra- and inter-observer reliability were good (κ value of 0.87 and 0.64 respectively). Conclusions This study demonstrates that US is a reliable tool for evaluating cartilage in RA and strongly supports the use of a new reliable semiquantitative MSUS scoring system for cartilage change. Disclosure of Interest None declared