isrctn.org Identifier: ISRCTN18186313.

Objective. The current treatment options for systemic-onset juvenile idiopathic arthritis (JIA) are methotrexate, steroids, and biologic agents. This study was undertaken to evaluate the safety of the orally active histone deacetylase inhibitor givinostat (ITF2357) and its ability to affect the disease.Methods. Givinostat was administered orally, for up to 12 weeks at a dosage of 1.5 mg/kg/day, to 17 patients with systemic-onset JIA who had had active disease for >1 month. Disease activity was clinically assessed using the American College of Rheumatology Pediatric 30 (ACR Pedi 30), ACR Pedi 50, or ACR Pedi 70 criteria for improvement and a systemic feature score. The primary goal was safety and the primary efficacy end point was the number of patients completing 12 weeks of treatment who were responders.Results. Givinostat was safe and well tolerated, with adverse events (AEs) being mild or moderate, of short duration, and self-limited. The 17 patients from the intent-to-treat population reported a total of 44 AEs, and the 9 patients in the per-protocol population reported a total of 25. Six AEs in 3 patients (nausea, vomiting, and fatigue) were related to the study drug, but each resolved spontaneously and no patient was withdrawn from the study due to drug-related AEs. In the per-protocol population at week 4, the improvement as measured by the ACR Pedi 30, ACR Pedi 50, and ACR Pedi 70, respectively, was 77.8%, 55.6%, and 22.2%, and this increased further to 77.8%, 77.8%, and 66.7% at week 12. The most consistent finding was the reduction in the number of joints with active disease or with limited range of motion.Conclusion. After 12 weeks, givinostat exhibited significant therapeutic benefit in patients with systemiconset JIA, particularly with regard to the arthritic component of the disease, and showed an excellent safety profile.Histone deacetylases (HDAs) are intracellular enzymes that maintain nucleosome histones in a state of deacetylation so that DNA remains tightly bound and inaccessible to transcription factors. Inhibition of HDAs results in hyperacetylation of histones, which allows for the sufficient unraveling of DNA for binding transcription factors and the synthesis of messenger RNA (1,2). There is increasing evidence that HDA inhibitors may also exhibit antiinflammatory properties (3). ITF2357 (recently named givinostat) is a hydroxamic acid containing an HDA inhibitor, which reduces the production and release of several proinflammatory cytokines (tumor necrosis factor ␣, interleukin-1␤ [⌱L-1␤], interferon-␥, IL-6, and IL-12) from human blood monocytes (4) as well as in models of autoimmune diseases and inflammation, including models of arthritis and synovial cell functions (5,6).Systemic-onset juvenile idiopathic arthritis (JIA) is an example of combined autoinflammatory and autoimmune disease. Reduction of the painful and destructive arthritis component of the disease remains a goal that has still not been achieved even with anticytokine parenteral therapies (7,8). The primary objective of t...

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Objective. The Outcome Measures in Rheumatology Ultrasound Task Force has recently started to work on the validation and standardization of musculoskeletal ultrasound (MSUS) examination in children in order to improve its applicability to joint examination. Methods. This was a prospective multicenter study performed by 4 experts in pediatric MSUS, who independently collected representative images using predefined scanning procedures of 4 joints (knee, ankle, wrist, and second metacarpophalangeal joint) in different predefined age groups. Researchers were allowed to use their own settings (B-mode and Doppler) in order to get the best quality image and highest sensitivity for low blood flow. Images were evaluated for quality parameters and an atlas was created with the best images. An equipment comparative study was performed by a single examiner using 2 different types of machines. Results. Sixty-four healthy children were scanned. The quality of evaluated images, obtained by predefined scanning positions, was highly comparable among the examiners. The B-mode images clearly showed age-related variations of joint findings, while Doppler images showed the presence of blood flow, particularly within the epiphyseal cartilage of the children at a younger age. There was a high to good level of consistency between images obtained from the 2 different ultrasound machines. Conclusion. The study shows a systematic method for ultrasound examination of children at different age groups. Additionally, a baseline collection of images was developed, showing blood vessels in the joints examined. The present study could provide a framework for ongoing MSUS studies as well as for clinical practice in pediatric rheumatology.

ObjectivesMusculoskeletal 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. MethodsThe decision on which US techniques to use, the components to be included in the Arthritis Care & ResearchThis article is protected by copyright. All rights reserved. Sonographic Definitions for Synovitis in Children 3 Significance and InnovationsMusculoskeletal Ultrasonography is an important tool for the clinical assessment and research in childhood arthritides Precise definitions for synovitis on ultrasonography in children are an essential prerequisite for the reliable use of this technology in the pediatric age group Ultrasonographic definitions for synovitis in children were developed and validated for the first time through an international consensus process

ObjectiveTo investigate the efficacy and safety of etanercept (ETN) in paediatric subjects with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA).MethodsCLIPPER is an ongoing, Phase 3b, open-label, multicentre study; the 12-week (Part 1) data are reported here. Subjects with eoJIA (2–17 years), ERA (12–17 years), or PsA (12–17 years) received ETN 0.8 mg/kg once weekly (maximum 50 mg). Primary endpoint was the percentage of subjects achieving JIA American College of Rheumatology (ACR) 30 criteria at week 12; secondary outcomes included JIA ACR 50/70/90 and inactive disease.Results122/127 (96.1%) subjects completed the study (mean age 11.7 years). JIA ACR 30 (95% CI) was achieved by 88.6% (81.6% to 93.6%) of subjects overall; 89.7% (78.8% to 96.1%) with eoJIA, 83.3% (67.2% to 93.6%) with ERA and 93.1% (77.2% to 99.2%) with PsA. For eoJIA, ERA, or PsA categories, the ORs of ETN vs the historical placebo data were 26.2, 15.1 and 40.7, respectively. Overall JIA ACR 50, 70, 90 and inactive disease were achieved by 81.1, 61.5, 29.8 and 12.1%, respectively. Treatment-emergent adverse events (AEs), infections, and serious AEs, were reported in 45 (35.4%), 58 (45.7%), and 4 (3.1%), subjects, respectively. Serious AEs were one case each of abdominal pain, bronchopneumonia, gastroenteritis and pyelocystitis. One subject reported herpes zoster and another varicella. No differences in safety were observed across the JIA categories.ConclusionsETN treatment for 12 weeks was effective and well tolerated in paediatric subjects with eoJIA, ERA and PsA, with no unexpected safety findings.

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