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Autoinflammatory diseases are rare disorders secondary to mutation of genes involved in the regulation of innate immunity. The main limitation to a better knowledge of Autoinflammatory diseases is related to the extreme fragmentation of the diagnosed cases that are spread over different centers and countries. The general aim of the Eurofever Project was to build an international registry on Autoinflammatory diseases. A web-based registry collecting baseline and cross-sectional clinical information on Autoinflammatory diseases is available in the member area of the PRINTO web-site (http://www.printo.it). The registry is open to all pediatric and adult Centers with a specific interest in Autoinflammatory diseases. The following monogenic autoinflammatory diseases were considered: Familial Mediterranean Fever (FMF), Cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), Blau syndrome, pyogenic arthritis, pioderma and acne (PAPA) syndrome, deficiency of IL-1 receptor antagonist (DIRA), NLRP12-mediated periodic fever. Information on CRMO, Behcet’s disease, PFAPA and undefined periodic fevers were also collected. 2916 patients, from 95 centers in 53 countries, have been enrolled in the registry during the first 36 months. Baseline demographic data (country of residence, disease onset, disease duration, mutations, family history ect) from all patients are now available. In 2275 (81%) complete information on clinical manifestations and responses to treatments is also available. The disease distribution of enrolled patients is: FMF 787 (621 with complete clinical data); TRAPS 237 (211 with complete clinical data); CAPS 207 (186 with complete clinical data); MKD 153 (133 with complete clinical data); Blau syndrome 62 (21 with complete clinical data); PAPA 19 (18 with complete clinical data); NLRP-12 mediated periodic fever 8 (6 with complete clinical data); DIRA and Majeed 3 and 2 patients, respectively (all with complete clinical data). Among multifactorial autoinflammatory diseases: PFAPA 564 (402 with complete clinical data); CRMO 392 (370 with complete clinical data); pediatric Behcet disease 84 (68 with complete clinical data) and 205 patients with undefined periodic fever (174 with complete clinical data). So far 8 papers involving 56 different authors and 32 centers have been published in high-rank international journals and other papers are in preparation. A large registry of patients with Autoinflammatory diseases is available and, despite the expiring of the initial grant, the enrolment is still ongoing with an increasing number of centers involved. Eurofever represents a good example of how a disease-oriented registry can provide relevant scientific answers to many unknown clinical aspects of ultra-rare diseases. This aspects was the main reason of the relevant success of the enrolment we have observed.

The term macrophage activation syndrome (MAS) identifies a severe and potentially fatal complication of s-JIA, and, more rarely of other rheumatic diseases. MAS share similarities in clinical features and laboratory abnormalities with primary and secondary heamophagocytic lymphohystiocytosis (HLH). Indeed it is currently classified among secondary HLH and the term rheuma-HLH has been used to indicate this condition. The clinical and laboratory similarities with primary genetic- caused HLH led to the hypothesis that pathogenic mechanisms leading to the typical features of MAS/rheuma-HLH are similar to those involved in primary HLH. We will review the evidence supporting this hypothesis; particularly the role of hyper-responses to TLR activation, of subclinical variants of genes involved in the cytotoxic pathways, and of the transient NK cytotoxicity defect induced by inflammatory cytokines. We will also present evidence on the role of IL-6, IL-1 and IFN-g in this syndrome and discuss the potential benefits of therapies targeted to these cytokines.

Juvenile Idiopathic Arthritis is a heterogeneous disease with significant variability in long-term outcome and treatment response; this occurs both between and within JIA subtypes, as defined by the current International League Against Rheumatism (ILAR) classification. There are currently no robust clinical or biological predictors of outcome or treatment response in JIA. Given that JIA is a complex genetic disorder, genetic studies provide an opportunity to address this issue, and whilst previous studies have often been limited by statistical power to identify the likely modest effect sizes, the recent establishment of a number of international consortia for JIA genetics has allowed this issue to be resolved. This presentation will summarize the current understanding of the genetic basis of JIA susceptibility, prognosis and treatment response and will describe how these genetic associations may further our understanding of the molecular mechanisms and immunological pathways involved in this disease. In addition it will provide insights into how we might utilise this data to progress towards the ultimate goals of predicting long-term disease outcomes at onset, predicting drug response, and move towards more targeted treatment options for children with JIA.

Comparison of epidemiological studies of JIA is challenging due to many influencing factors, mainly differences in classification criteria or study designs (e.g. population-based, hospital-based, questionnaires, registry data). Recently, longitudinal cohort studies have provided important contributions to the understanding of the disease course of JIA in the long run. Latest advances in research of incidence and prevalence of JIA will be highlighted and discussed to facilitate understanding the consequences of epidemiological knowledge of the disease.

Macrophage activation syndrome (MAS) is a life-threatening complication of inflammatory disease, occurring secondary to a complex interplay of genetic factors, drugs, infectious agents and immunological anomalies. Early identification and aggressive treatment are mandatory to prevent fatal evolution. Precipitating factors should be looked for and eventually removed such as infections (leishmania, EBV, Parvo B19…) or drug exposure. Epstein Barr Virus (EBV) is a major cause of MAS and anti-EBV therapies can be helpful to control MAS. First line therapies usually include high-dose steroids associated to cyclosporine. In the context of primary hemophagocytic lymphohistiocytosis (HLH), bone marrow transplantation is the only treatment able to cure the disease. In inflammatory disease with secondary HLH, a few case reports indicate an efficacy of anti-cytokine treatment (anti-IL1, anti-IL6, anti-TNFα). However, a role of these cytokines in MAS development remains unproven. To investigate whether the IL-1 pathway might contribute to MAS, we compared IL-1RA-/- to wild type mice after stimulation with CpG, a TLR9 activator. TLR9-induced MAS was similar in the two groups, suggesting that IL-1 excess is not a major inducer of MAS. More interestingly, recent data implicate IFNγ as a crucial factor in MAS onset. Thus, the inhibition of secreted IFNγ might represent an interesting therapeutic avenue worthy of further investigation.

With the introduction of biologics in pediatric rheumatology the options for effective treatment have increased considerably. Consequently the majority of children with JIA reach a remission in earlier stages of their disease and the impact on joint health, ambulation and functional ability of JIA have changed accordingly. This brings new perspectives for the (allied) health professional in the field of pediatric rheumatology. "Co-creation", family centered care, even family integrated care models are currently explored in this field. Multi-level; composed outcome measures (PRInTO-outcomes), patient rated outcome measures (PROM,s) are increasingly used in research and outcomes research, emphasis on family centered approaches deliver new measures such as the Family Needs Inventory What are the paradigm shifts we will face the coming decade, how does it influence our professional attitudes, skills and knowledge? What will be the added value of the (allied) healthprofessional in the coming decade?

EU Paediatric Regulation was adopted by the European Parliament and the Council in December 2006. First meeting of the Paediatric Committee took place in July 2007. 1. Paediatric investigation Plans (PIPs) In 2007-2013 The European Medicines Agency (EMA) and its Paediatric Committee have agreed more than 600 Paediatric Investigation Plans (PIPs) with pharmaceutical companies, to provide data on the efficacy and safety of medicines for diseases of children. · For treatment of JIA PIP was agreed for the following substances: abatacept, adalimumab, anakinra, anti-BAFF antibody, anti-IL-6 antibody, anti-IL17 antibody, anti-IL-17A antibody, apremilast, baricitinib, canakinumab, certolizumab, denosumab, etanercept, givinostat, golimumab, olokizumab, sarilumab, tocilizumab, tofacitinib and ustekinumab. · For treatment of SLE in children PIP was agreed for anti-BAFF, belimumab and epratuzumab. · For treatment of CAPS PIP was agreed for anakinra, anti-IL-1beta antibody and canakinumab. 2. Clinical trials More paediatric clinical trials were done (data from EudraCT, accessible at the European Clinical Trials Register): 3. New authorised indications for children · 12/11/2009: canakinumab for treatment of CAPS. · 25/08/2008: adalimumab - treatment of active polyarticular juvenile idiopathic arthritis in adolescents from 13 to 17 years of age. · 20/01/2010 abatacept - treatment of moderate to severe active polyarticular juvenile idiopathic arthritis in paediatric patients 6 years of age and older. · 18/03/2011 adalimumab - treatment of active polyarticular juvenile idiopathic arthritis in the paediatric population aged from 4 to 12 years. · 01/08/2011: tocilizumab - treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older. · 24/08/2011: etanercept - polyarticular juvenile idiopathic arthritis (JIA) from the age of 2 years. · 24/08/2012: etanercept - treatment of RF+ and RF- polyarthritis, extended oligoarthritis from 2 years of age, psoriatic arthritis and ERA from 12 years of age. · 17/01/2013 - adalimumab - treatment of active polyarticular juvenile idiopathic arthritis in the paediatric population aged from 2 to 4 years old. · 25/04/2013 - tocilizumab - treatment of polyarthritis (RF+, RF- and extended oligoarthritis) from 2 years old (EC decision pending at the time of abstract submission). 4. A network of paediatric research networks Enpr-EMA works by fostering collaboration from within and outside the European Union (EU), including between members, patients associations, academia and the pharmaceutical industry.) PRINTO and JSWG of PRES are members of Enpr-EMA. 5. Expert meetings at EMA: Paediatric rheumatology (2009, 2010), Gastroenterology and rheumatology (2010). 6. Development of scientific guidelines (JIA, SLE, GIOP). 7. Pharmacovigilance ENCEPP - (PharmaChild protocol agreed).

The enormous number and diversity of microorganisms in the human gastrointestinal tract support the host in many functions such as digestion of complex carbohydrates. The relationship between the gut microbiota and energy homeostasis, metabolic dysfunction and inflammation and their role in the pathogenesis of obesity.-related disorders is increasingly recognized. Obesity developing in genetically or diet-induced obese mice is characterized by impressive changes in the composition and metabolic function of the gut microbiota. Importantly, colonization of germ-free mice with an "obese-gut-derived" microflora results in a much greater increase in total body fat and leads to obesity. Similar alterations as in experimental models have been observed in human obesity. The gut microbiota is able to directly regulate host gene expression and thereby could control host energy expenditure and storage. This may take place by various mechanisms such as regulation of Fiaf, AMPK or short chain fatty acids. Furthermore, it is increasingly recognized that diet may have a fundamental effect on the composition of our microbiota. The innate immune system is another important player controlling microbiota composition. Animals deficient for toll-like receptor 5 (TLR5) or certain members of inflammasomes such as Caspase1 or ASC develop a dysbiosis which is associated with obesity, metabolic syndrome and fatty liver disease. Whereas knowledge in various models is increasing, data in humans are still in its infancy. This is especially true for interventional studies manipulating the gut microbiota e.g. by using antibiotics, pro- or prebiotics. A first human study using fecal transplantation recently showed that insulin sensitivity might be improved via such a strategy. Overall, data suggest an important role for the microbiota in metabolic dysfunction, type 2 diabetes and obesity.

Pain syndromes often provide the clinician with the most complex challenges in understanding the condition as well as working out the maintaining factors and therefore how to support these patients back to function and recovery. These young people are often very disabled by these conditions and struggle to function in all aspects of their life including school and socially. The bio-psychosocial model of management involving all aspects of their life is the most successful and this often requires an effective multidisciplinary team in order for the outcome to be effective. The most important aspects of treatment are for the clinicians to be clear about the diagnosis and to stop investigations looking for a cause. Secondly the child and family need to realise that the most effective approach is based on ‘active participation’ in all aspects of the therapy with the goal being selfmanagement and participation in all aspects of life fully. Treatment should focus upon the young person completing exercises in order to regain movement, strength and stamina resulting in increased function. Work with desensitisation is also important, but not alone from regaining movement and strength. Learning specific pain management techniques, active relaxation and how to pace activities is also important. It is important to focus on solutions, recovery and independent self-management rather than causes as this can prevent recovery. Reintegration into normal activity is important and school attendance should be prioritised followed by returning to sport and other physical activities. The outcomes of effective management is very positive in young people providing they engage with the understanding that they are the solution to the management of the pain.

Since the middle 1990s biologics have been available for rheumatic diseases. The initial experiments showed efficacy for symptoms and signs but concern was expressed about tachyphylaxis and absence of a true DMARD effect. Combining the antibodies with methotrexate answered some of these criticisms and since that time the number of agents available for rheumatoid arthritis, psoriatic arthritis and spondyloarthropathy has grown. It is clear these agents work, what is less clear is how they should be used to produce optimum cost benefit. The ever expanding market has attracted a large number of pharmaceutical players to this area and this shows no sign of abating. Also there are number of new drugs including oral synthetic DMARDs becoming available.

The autoinflammatory syndromes are a group of multisystem disorders characterized by recurrent episodes of fever and systemic inflammation affecting the eyes, joints, skin, and serosal surfaces. These syndromes differ from autoimmune diseases by several features, including the periodicity whereas autoimmune diseases are progressive, and the lack of signs of involvement of adaptive immunity such as association with HLA aplotypes, high-titer autoantibodies or antigen-specific T cells. Thus, autoinflammatory syndromes are recognized as disorders of innate immunity. This definition is supported by the a dramatic therapeutic response to IL-1 blocking. Indeed, the rapid and sustained response to a reduction in IL-1 activity on an "ex adjuvantibus" basis is the best hallmark of most of these diseases. Due to the rarity of these conditions, most of the studies aimed to unravel the pathogenic consequences related to the mutation of genes involved in inherited autoinflammatory diseases were based on the analysis of in vitro transfected cells or animal models. These approaches has the clear advantage to facilitate the availability of material for these studies and also to reduce the variability associated to clinical and genetic variables (type of mutation, active versus inactive disease, ongoing treatment, etc..). On the other hand the use of patients' primary cells strongly increase the possibility that the observed phenomena could be indeed pertinent to the pathogenesis of the disease and not influenced by possible artifacts linked to the study of transfected cells or animal models. In the present lecture we will review the contribution that the study of primary cells from patients affected by inherited autoinflammatory diseases gave to the understanding of the role of IL-1 in the pathogenesis of these disorders.

Fevers are common in childhood, usually due to infections. Some children however experience recurrent episodes of seemingly unprovoked fevers. These so-called periodic fever syndromes are rare diseases. Clinically they are characterized by generalized inflammation and different combinations of localized tissue inflammation. Skin and joints are often affected in these patients and the long-standing inflammation can lead to irreversible organ damage due to tissue deposition of inflammatory amyloid proteins. Especially the kidney is vulnerable tot his so-called AA-amyloidosis. The spontaneous sterile inflammation in the absence of autoantibodies places the periodic fever syndromes in the same category as systemic juvenile idiopathic arthritis: the group of autoinflammatory diseases. Often these are genetically determined. Over the past 15 years genetic defects have been identified underlying more than twenty such genetic autoinflammatory diseases. These are disorders like Familial Mediterranean Fever, caused by mutations in the MEFV gene, TNF-receptor associated periodic syndrome (TRAPS), caused by mutations in the TNFRSF1A gene and the Chronic Infantile Neurological Cutaneous Articular (CINCA) syndrome, caused by mutations in the NLRP3 gene. Identification of the responsible genes has led to understanding of the pathophysiology and hence to effective targeted therapy. Interleukin-1 has proved to be the central mediator in many of these disorders. This finding in the congenital autoinflammatory diseases has led to novel therapies in more common disorders like interleukin-1 blockade in systemic Juvenile Idiopathic Arthritis. The rarity of the periodic fever syndromes hampers evidence based therapy. International collaboration in the EUROFEVER network has enabled us to better define the clinical picture of these disorders and to select targets for therapeutic research. However, many children currently defy genetic diagnosis. Next generation genetic sequencing efforts will hopefully identify the cause of inflammation in this group of patients. The functional consequences of autoinflammatory diseases are primarily related to the unpredictable fever episodes. However irreversible sequelae, such as hypertrophic arthropathy, chronic renal failure, impaired vision or hearing do occur. Since these are largely preventable by adequate control of inflammation, effective therapy is essential.

Antiphospholipid antibodies (aPL) are both diagnostic markers for, and pathogenic drivers of, antiphospholipid syndrome (APS). Beta 2 glycoprotein I (Beta2GPI)-dependent aPL, the most important subset, mediate different--and not necessarily alternative--thrombogenic mechanisms, mainly on the basis of their reactivity with Beta2GPI expressed on cells that participate in the coagulation cascade. In vivo experimental models showed that Beta2GPI cannot be detected in vascularized organs in resting conditions, while it can be over-expressed after pro-inflammatory stimulus. In this condition autoantibodies recognize the molecule, fix complement (C') and eventually induce clotting. This finding is in line with the observation that although the presence of aPL is a necessary pre-condition, APS-associated clotting is triggered by an additional 'second hit', frequently related to innate inflammatory immune responses. Recurrent pregnancy complications associated with aPL cannot be explained solely by thrombosis, and alternative pathogenic mechanisms have been reported. Although one in vivo model of fetal loss supports a mechanism of aPL-mediated acute placental inflammation, other models and the histopathological examination of APS placentae do not support an inflammatory signature. Beta2GPI can be detected on endothelial cells of uterine vessels in resting conditions and its presence is increased during pregnancy in uterine endothelium and trophoblast. This finding does support the hypothesis that Beta2GPI -dependent aPL recognize their antigen on placental tissues. There is evidence that the antibodies may inhibit the growth and differentiation of trophoblasts, and eventually cause defective placentation so explaining the APS obstetric manifestations. Why antibodies with similar antigen specificity produce different clinical manifestations is not clear. The formation of immune complexes on the membrane of cells with different biological functions may at least in part explain the diverse effects mediated by the autoantibodies (i.e. clotting versus defective placentation). Altogether this finding strongly supports the pivotal role of Beta2GPI as the main tissue target for aPL. Accordingly, new approaches have been tried in order to interfere with the antibody binding and its consequences. A synthetic peptide displaying a similarity in the PL-binding region of the Vth domain of the Beta2GPI was shown to compete with the molecule binding to the membrane of cells involved in the pathogenesis of the syndrome (i.e. endothelial cells, monocytes and trophoblasts). The passive infusion of the peptide was protective against the effect of polyclonal human APS IgG fractions on experimental thrombus formation and fetal loss induction. Moreover, a human monoclonal antibody against the immunodominant epitope of the Beta2GPI (Domain I) was shown to induce fetal loss and to trigger clotting by fixing C' in naive mice. A similar monoclonal antibody lacking the CH2 fragment in the Fc gamma portion was still reacting with the Beta2GPI but no more able to activate C'. The C' non-fixing monoclonal antibody was protective by competing with the pathogenic one when passively infused in naive mice and evaluated for both the induction of thrombus formation and the induction of fetal loss.

Background Childhood-onset SLE is a complex multiorgan disease. In order to judge the need of medical intervnetions and the patient benefits from them, measurement disease activity and damage are key. Furthermore, important improvement and deterioration of disease needs to be ascertained. Such measurement are the basis for clinical trial aimed at identifying improved medications and are needed to judge the benefits of medical interventions in general.

Cytokines are pleiotropic mediators that play a major role in inducing and orchestrating the inflammatory and the immune response. They play a major role in the response to damage or infections. In some pathological condition abnormal regulation of the production of cytokines leads to pathological events and subsequent damage to target tissues. Dissecting the role of each single mediator in the plethora of cytokines and in the complex networks has been one of the aims of biomedical research that has led to relevant applications in rheumatic diseases. In the presentation we will briefly review the evidence leading to the identification of the role of some cytokines (IL-1, IL-6 and TNF) as key mediators and therapeutic targets in pediatric rheumatic diseases.

We can expect that a better understanding of the pathogenesis of systemic lupus erythematosus (SLE) will eventually lead to improved treatments for this devastating disorder (’translational medicine’). And if lupus is not a single disease entity, then different treatment regimens might be appropriate in different patients (’personalized medicine’). As one approach to improving our understanding of why some people develop lupus, we are interested in the identification and analysis of monogenic (i.e. Mendelian) forms of SLE - thinking that they will not only provide clues to disease causation in specific cases, but that they will also help to define general molecular concepts of immune tolerance/dysfunction in humans, and thus inform the experimental approaches of other researchers (by highlighting potentially important disease pathways e.g. the ‘type I interferonopathies’). Drawing on aw ell-proven strategy taken in other ‘complex diseases’ (e.g. certain types of cancer, motor neuron disease, Parkinson disease, Alzheimer disease etc.), we hypothesise that populations of children affected by lupus will likely be enriched for Mendelian forms. We are therefore harnessing the power of nextgeneration sequencing technology to identify highly penetrant genetic susceptibility loci for juvenile SLE. In this talk, I will discuss our strategy, outline the challenges involved in such an approach, and highlight some recent successes. Disclosure of interest None declared.

The treatment of paediatric rheumatic diseases has made great progress in the last decade. The introduction of the biologicals meant (after the introduction of MTX) the second therapeutic revolution. This together with many improvements in related areas has greatly improved the quality of life of patients with rheumatic diseases. At present however, despite the introduction of more biological agents directed at immune targets the progression has stalled. The next challenge will be to: 1) Better understand the immune pathogenesis underlying the heterogeneity of the disease. 2) Identify patients at risk at the onset of disease and stratify them according to risk factors. 3) Personalize treatment based on their risk profiling. 4) Develop strategies that are aimed not only at suppressing disease but also at maintaining disease remission after withdrawing immune suprresion. Over the last years much progress has been made in all these area's. In this presentation we will discuss this progress, focusing on a better understanding of the mechanisms of immune tolerance, leading to new targets for intervention.