Bas Vastert

Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells

During the last decade research has focused on the application of FOXP3(+) regulatory T cells (Tregs) in the treatment of autoimmune disease. However, thorough functional characterization of these cells in patients with chronic autoimmune disease, especially at the site of inflammation, is still missing. Here we studied Treg function in patients with juvenile idiopathic arthritis (JIA) and observed that Tregs from the peripheral blood as well as the inflamed joints are fully functional. Nevertheless, Treg-mediated suppression of cell proliferation and cytokine production by effector cells from the site of inflammation was severely impaired, because of resistance to suppression. This resistance to suppression was not caused by a memory phenotype of effector T cells or activation status of antigen presenting cells. Instead, activation of protein kinase B (PKB)/c-akt was enhanced in inflammatory effector cells, at least partially in response to TNFα and IL-6, and inhibition of this kinase restored responsiveness to suppression. We are the first to show that PKB/c-akt hyperactivation causes resistance of effector cells to suppression in human autoimmune disease. Furthermore, these findings suggest that for a Treg enhancing strategy to be successful in the treatment of autoimmune inflammation, resistance because of PKB/c-akt hyperactivation should be targeted as well.

Time to share

In the following a brief commentary is given on a new European project that aims to provide the European countries with recommendations for the care of children and yound adults with rheumatic diseases. These recommendations will be based on surveys sent to PRINTO members and systematic literature reviews. Surveys on current local standard of care and best practice will be send to PRINTO members in EU member states. The success of this project largely largely depends on information provided by individual centers from our existing PRINTO and PReS networks. We would therefore like to ask your collaboration in completing and returning these surveys which will be circulated March April 2013.

Regulatory T cells in autologous stem cell transplantation for autoimmune disease

Since a decade autologous stem cell transplantation (ASCT) is successfully performed to treat patients with severe autoimmune disease. However, the mechanism of action of this intervention remains largely unknown. Scarce data from animal studies and human clinical trials indicate that, besides extensive immune ablation, restoration of regulatory immune networks is of critical importance. This review focuses on the role of naturally occurring and induced regulatory T cells in controlling immune reconstitution and restoration of immune tolerance and in preventing relapses of disease following ASCT.

European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupus erythematosus: the SHARE initiative

Childhood-onset systemic lupus erythematosus (cSLE) is a rare, multisystem and potentially life-threatening autoimmune disorder with significant associated morbidity. Evidence-based guidelines are sparse and management is often based on clinical expertise. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) was launched to optimise and disseminate management regimens for children and young adults with rheumatic diseases like cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of cSLE. In view of extent and complexity of cSLE and its various manifestations, recommendations for lupus nephritis and antiphospholipid syndrome will be published separately. Recommendations were generated using the EULAR (European League Against Rheumatism) standard operating procedure. An expert committee consisting of paediatric rheumatologists and representation of paediatric nephrology from across Europe discussed evidence-based recommendations during two consensus meetings. Recommendations were accepted if >80%u2009agreement was reached. A total of 25 recommendations regarding key approaches to diagnosis and treatment of cSLE were made. The recommendations include 11 on diagnosis, 9 on disease monitoring and 5 on general treatment. Topics included: appropriate use of SLE classification criteria, disease activity and damage indices; adequate assessment of autoantibody profiles; secondary macrophage activation syndrome; use of hydroxychloroquine and corticosteroid-sparing regimens; and the importance of addressing poor adherence. Ten recommendations were accepted regarding general diagnostic strategies and treatment indications of neuropsychiatric cSLE. The SHARE recommendations for cSLE and neuropsychiatric manifestations of cSLE have been formulated by an evidence-based consensus process to support uniform, high-quality standards of care for children with cSLE.

Biologic treatment of pediatric rheumatic diseases: are we spoilt for choice?

Approximately 15 years ago the first biological treatment for juvenile idiopathic arthritis (JIA) was introduced. Since the introduction of the TNF receptor fusion protein etanercept in 1998, now more than seven biologics are now registered, or under study for JIA. Notably, these biologics were initially not developed for JIA but derived from the experience in the treatment of adult rheumatic diseases. This simple fact still has major consequences on the prescription and reimbursement of biological treatments in pediatric rheumatic diseases (PRD). As an endorsement for clinical research in pediatric diseases, the EU launched a new act in 2006, the Pediatric Rule [101]. This rule states that drugs tested for a specific condition in adults are also required to be tested in related pediatric diseases [101]. Therefore, when pharmaceuticals submit a registration proposal to EMA, a Pediatric Investigational Plan must be included. This means increased efforts and costs for pharmaceutical companies. Despite the efforts of the EMA, many national and local institutional review boards are still reluctant to approve medication studies in children. In The Netherlands, therapeutic trials in children are only allowed under strict regulations. Children should benefit from the study, risks have to be negligible and the burden minimal. A proposal to amplify these strict regulations encountered a lot of resistance among members of the College of Human Rights, claiming to protect young children for medical trials. So the question arises: are pediatric rheumatologists convinced that therapeutic trials in children with rheumatic diseases are required in order to enlarge the spectrum of biological therapy, or do the current therapies provide s ufficient choices in the treatment of PRD?

Evidence based recommendations for genetic diagnosis of Familial Mediterranean Fever.

Familial Mediterranean Fever (FMF) is a disease that starts in childhood and can lead to significant morbidity. In 2012, a European initiative called SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) has been launched to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. For FMF, attention was focused on genetics.

Update on research and clinical translation on specific clinical areas from biology to bedside: Unpacking the mysteries of juvenile idiopathic arthritis pathogenesis

In the past decades, we have gained important insights into the mechanisms of disease and therapy underlying chronic inflammation in juvenile idiopathic arthritis (JIA). These insights have resulted in several game-changing therapeutic modalities for many patients. However, additional progress still has to be made with regard to efficacy, cost reduction, minimization of side effects, and dose-tapering and stop strategies of maintenance drugs. Moreover, to really transform the current therapeutic strategies into personalized medicine, we need validated biomarkers to translate increased insights into clinical practice. In this article, we describe recent developments in JIA research and outline how clinical innovations need to go hand in hand with basic discoveries to really effect care for patients. Facilitating the transition from bench to bedside is crucial for addressing the major current challenges in JIA management. When successful, it will set new standards for a safe, targeted, and personalized medicine in JIA.

FRI0271 Final Evidence-Based Recommendations for Diagnosis and Treatment of Paediatric Vasculitides

Background The paediatric vasculitides are a group of rheumatic diseases characterized by blood vessel inflammation. Several vasculitic syndromes can be distinguished based on the size of the involved vessels as well as the specific symptoms. Incidence of these syndromes is low and evidence-based paediatric guidelines are lacking. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) is a project that aims to develop European evidence-based guidelines for diagnosis and treatment of these and other rare paediatric rheumatic diseases (PRD). Objectives To develop evidence-based recommendations for diagnosis and treatment of paediatric vasculitides, i.e. Kawasaki Disease (KD), Henoch Schönlein Purpura (HSP), Polyarteritis Nodosa (PAN), Granulomatosis with Polyangiitis (GPA), Eosinophilic granulomatosis with Polyangiitis (EGPA) and Takayasus Arteritis (TA). Methods A systematic review of literature was conducted (results presented at PReS 2014), from which evidence-based recommendations were derived. A European expert committee evaluated these recommendations, both by online surveys and by discussion using the nominal group technique1 during several in-person consensus meetings in Genoa (Italy, March ’14, results presented at PReS 2014), Utrecht (the Netherlands, January ’15) and Barcelona (Spain, March ’15). Recommendations were accepted for the final guidelines if more than 80% agreement was reached. Results Evidence from literature and expert opinion led to the formulation of recommendations for the different paediatric vasculitides. Adding to the 44 statements accepted with more than 80% consensus in Genoa, an additional 78 statements were accepted in Utrecht. Included statements ranged across different topics, including criteria for diagnosis, referral indications, clinical and laboratory parameters, imaging and treatment of the different vasculitic syndromes. Statements for discussion in Barcelona will focus on general and interdisciplinary aspects of care for children with vasculitis and other PRDs. Conclusions SHARE aims to provide minimal standards of care for PRD. We present the final recommendations for diagnosis and treatment of paediatric vasculitides. These recommendations will contribute to a more uniform and evidence-based foundation for diagnosis and treatment of KD, HSP, PAN, GPA, EGPA and TA in children. References Harvey N, Holmes CA. Nominal group technique: an effective method for obtaining group consensus. Int J Nurs Pract. 2012; 18:188-94 Acknowledgements This project is supported by a grant from European Agency for Health and Consumers (EAHC), grant number 2011 1202. Disclosure of Interest None declared

Transcription factor motif enrichment in whole transcriptome analysis identifies STAT4 and BCL6 as the most prominent binding motif in systemic juvenile idiopathic arthritis

BackgroundThe term systemic juvenile idiopathic arthritis (sJIA) describes an autoinflammatory condition characterized by arthritis and severe systemic inflammation, which in later stages can transform into interleukin (IL)-17-driven autoimmune arthritis. IL-1 antagonists have been used with good efficacy in the early stages of sJIA.MethodsA whole transcriptome analysis of peripheral blood RNA samples was performed in six patients with sJIA and active systemic disease, before initiating treatment with the IL-1β receptor antagonist anakinra, and after induction of inactive disease, compared with a single-sample control cohort of 21 patients in several clinical stages of sJIA activity. Whole transcriptomes were compared longitudinally and interindividually including gene ontology and motif enrichment analysis of differentially expressed genes.ResultsThere were 741 transcripts were identified using a threshold with a p value <0.01 and a fold change >u20092. HLADRB1 and CD74 were identified as the most strongly upregulated genes in inactive compared to active disease; CD177 expression was significantly enhanced in active disease compared to inactive disease. Motif enrichment analysis revealed STAT4, BCL6, and STAT3 as the most prominent transcription factors that were present during active disease. In addition, strong upregulation of the major histocompatability complex II (MHCII) ligand CD74 was found in both active and inactive sJIA compared to healthy controls.ConclusionUsing transcription factor motif enrichment, this study identifies novel putative pathways in sJIA (STAT4, BCL6) implicating B cell activation at an earlier stage than predicted in refractory disease. The implication of BCL-6 dependent pathways argues for occurrence of autoimmunity early within the process of sJIA chronification. Transcriptional regulation of HLA-DRB1, a recently described independent genetic risk factor, in combination with its cooperating partner CD74 in patients where sJIA is confirmed, supports pathogenic involvement in alterations in antigen presentation during sJIA.

Monocytes and neutrophils in the inflammatory cascade of systemic onset Juvenile Idiopathic Arthritis

8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases