Explore the vast range of titles available.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disorder in children and is also a major cause of acquired disability and quality of life impairment in childhood. Children with oligoarticular JIA are usually treated with NSADS and intraarticular steroid injections. For children with polyarticular course JIA, methotrexate (MTX) is the drug of first choice since it provides significant clinical benefits, with an acceptable toxicity profile. For children not responding to MTX, the introduction of the biologic agents has determined a substantial advantage for the therapy of JIA since for the first time we have now drugs able to selectively block key components of the inflammation cascade.Biologic agents can be globally divided into 2 categories: drugs able to block the tumor necrosis factor (TNF) (etanercept, infliximab, adalimumab and others) and drugs with different mechanism of action (eg abatacept, tocilizumab, anakinra, canakinumab ecc). In general biologic agents, also for their elevated cost, have to administered in children with severe arthritis non responsive to conventional therapies, primarily MTX.The real novelty in these last years, has been the availability of biologic agents to be specifically used for the treatment of systemic JIA where, along with arthritis, children have systemic manifestations such as fever, rash, serositis, lymphadenopathy etc. These new drugs are indeed able to block selectively molecules that has been shown to be pivotal in the inflammatory process such as IL6 (tocilizumab) and IL 1 (anakinra, canakinumab and others)Most of the biologic agents have been tested (or are currently under study) thanks to the involvement of the Pediatric Rheumatology International Trials Organisation (PRINTO at www.printo.it) and of the Paediatric Rheumatology Collaborative Study Group (PRCSG at www.prcsg.org).This review will present a practically orientated overview of the “state of the art” for the treatment of JIA and the other major paediatric rheumatic disases including an overview on safety aspects.Disclosure of InterestN. Ruperto Grant/research support from: The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the following industries: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Speakers bureau: The undersigned Dr Nicolino Ruperto received honoraria for consultancy or speaker's bureau from the following pharmaceutical companies: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, Vertex.

This lecture will present a general overview, with pros and cons, of the different study design that could be employed for drug evaluation in pediatric rheumatic diseases.Among the multitude of study designs that could be considered in pediatric rheumatology, the major trial designs are the classic parallel randomized clinical trial (RCT) with placebo or active comparator and the randomized withdrawal design. While the parallel design still remain the gold standard for establishing the efficacy and short-term safety of an experimental agent, disadvantages include ethical concerns due to the use of placebo in children with chronic condition for which alternative treatments are available. The option of using an active control is not feasible due to the high sample size that are required by these kind of trial. The double-blind, controlled, randomized withdrawal design was proposed for the first time by Dr Lovell and Dr Giannini for use in pediatric rheumatology studies in particular for juvenile idiopathic arthritis. Eligible children are treated in an open label fashion with the experimental therapy to be tested in the trial for a few months after which responders (typically defined as those demonstrating an ACR Pediatric 30 response) are randomized in a double-blind fashion either to continue the experimental therapy or to switch to placebo. In this segment of the study, called the double-blind withdrawal phase, patients who demonstrate a pre-defined definition of disease worsening (e.g. “flare”) are withdrawn from the double-blind withdrawal phase and usually re-treated with the experimental therapy in an open label fashion. The withdrawal design has proven to be very effective design and has been used in nearly all recent trials of biologic agents in children with JIA. Data gathered by use of this design led to the approval of biologic agents for children with JIA by both the FDA and EMA.Disclosure of InterestN. Ruperto Grant/research support from: The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the following industries: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Speakers bureau: The undersigned Dr Nicolino Ruperto received honoraria for consultancy or speaker's bureau from the following pharmaceutical companies: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, Vertex.

Objective To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. Methods A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. Results Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. Conclusions In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.

Juvenile dermatomyositis (DM) is a chronic disease that, like its adult equivalent, primarily affects skin and muscles. Despite improved disease outcomes with treatment strategies used over the last few decades, it is still associated with significant morbidity and mortality. Treatment for both children and adults is based on case reports and retrospective studies since very few controlled trials, conducted in small patient populations, have been performedThere is strong clinical consensus that corticosteroids represent the first-line treatment of choice for juvenile DM. In steroid resistant or steroid dependent cases, an immunosuppressive drug is added as steroid sparing agent. The choice of the immunosuppressive agent relies mostly on the experience of the physician and varies widely between countries. Two of the most common immunosuppressors used in the treatment of juvenile DM are methotrexate and cyclosporine. It has however been suggested that a more aggressive therapy combining steroids and an immunosuppressive drug at disease onset could result in a better outcome.Recently the Paediatric Rheumatology International Trials Organisation (PRINTO) completed a randomized clinical trial in order to establish if, in newly diagnosed juvenile DM cases, combined treatment with steroids and methotrexate or steroids and cyclosporine has a safety and an efficacy profile which is superior to steroid monotherapy. The trial showed that combined therapy with prednisone and either cyclosporine or methotrexate was more effective than prednisone alone. The safety profile and the steroid sparing effect favored the combination of prednisone + methotrexate.The current evidence from the literature for the treatment of juvenile DM will be revised.Disclosure of InterestN. Ruperto Grant/research support from: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth. The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the industries mentioned in this section. This money has been reinvested for the research activities of the hospital in a fully independent manners besides any committment with third parties., Consultant for: Honoraria for consultancy: Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Servier, Takeda, Vertex.,, Speakers bureau: Abbott, AbbVie, Amgen, Biogenidec, Astellas, BMS, CD-Pharma, Hoffman-La Roche, Pfizer

ObjectiveTo evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers.MethodsA web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included.Results136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss.ConclusionsPatients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.

The existence of large networks such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), the Pediatric Rheumatology European Society (PRES) and more recently the Childhood Arthritis (Research Alliance (CARRA) has greatly facilitated the possibility of implementing collaborative studies either academic or in collaboration with pharmaceutical companies in the field of pediatric rheumatology. In the last few years PRINTO has concentrated its efforts to provide facilities to its membership for the conduct of international research projects. The ongoing initiative are as follow: A pharmacovigilance registry for children with juvenile idiopathic arthritis (JIA) treated with biologics ± methotrexate and financed by the European Union which has collected data for almost 6000 JIA children. A sub-project called Abirisk, in collaboration with an adult international consortium financed by IMI, is evaluating the development of antibodies against biologic drugs and its correlations with safety and efficacy results. The Eurofever registry has collected clinical and laboratory data for almost 3,000 children and adults with auto-inflammatory syndromes. The EPidemiology, treatment and Outcome of Childhood Arthritis throughout the world (EPOCA) study has collected has the goal to define and compare the epidemiology, treatment and outcome of the JIA categories around the world. The project has collected more than 7,000 JIA patients and 2,000 healthy controls. Another project has the goal to develop new classification criteria for macrophage activation syndromes (MAS) in systemic JIA and has collected 360 MAS cases and 750 controls (400 systemic JIA cases without MAS and 350 sepsis). In addition PRINTO is working to update information for families of children with pediatric rheumatic diseases (www.pediatric-rheumatology.printo.it) and characterize the current pattern of care through the Share project financed by the EU. The PRINTO networks can be seen as a model for international cooperation in rheumatology and other paediatric subspecialties. Disclosure of Interest N. Ruperto Grant/Research support from: The Gaslini Hospital, which is the public Hospital where I work as full time employee, has received contributions to support the PRINTO research activities from industries: Abbott, BMS, “Francesco Angelini”, GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth, Conflict with: Abbott, AbbVie, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma,Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Vertex Pharmaceuticals Servier DOI 10.1136/annrheumdis-2014-eular.6138

Orphan diseases are an heterogeneous group of 6000 disorders which span from rare cancers to genetic syndromes, to auto-immune diseases. The current definition identify as rare disease conditions with a prevalence less that 1:2000 (1999 Orphan Drug regulation); the definition of ultra rare refers to a prevalence of less than 1:1,000,000. More than 400 orphan diseases are currently treated with a drug which has a specific indication; 15 new orphan indication have been designated in 2012. In the Orphanet database (www.orphanet.org) there are 488 ongoing clinical trials registered for 304 rare diseases or group of rare diseases (most of whom are trials in cancers). The majority of the trials are driven by pharmaceutical companies with about 25% having a public sponsor. A recent methodology workshop by the European Clinical Research Infrastructure Network (ECRIN) was dedicated to issue recommendations for performing clinical trials in rare diseases. The recommendations state to apply standard statistical methodologies, with proper sample size calculations, for rare diseases in general. For ultra rare diseases there was a suggestion to move toward adaptive licensing with re-assessment of the findings every 3 to 5 years with a systemic data collections. To enlarge enrollment international networking should be the standard despite the several difficulties now encountered with multi-national ethics committee approval, insurances, funding etc especially with studies conducted by academia. Appropriate endpoints should be applied with surrogate markers to be used only when appropriately justified and possibly validated. Registries lead by patient’s organization/academia/industries possibly, linked together, should be the ideal situation for data collection. This lecture will describe the current challenges for running clinical trials in rare diseases in rheumatology. Disclosure of Interest None Declared

The evaluation of efficacy in clinical trials in pediatric rheumatology have been classically based on physician’s centered measures and on patient’s reported outcome (PRO) The efficacy measures could then be divided into those who could be applied across diseases such as the physician’s evaluation of disease activity usually on a 10 cm Visual Analogue Scale (VAS) or on a 21 circle VAS, the functional ability tools such as the Childhood Health Assessment Questionnaire (CHAQ) or the evaluation of health related quality of life (HRQOL) such as the Child Health Questionnaire (CHQ), and parent’s/patients global assessment of overall well-being and pain usually on VAS and more recent newer tools such as the Juvenile Arthritis Multidimensional Assessment Report (JAMAR). For the disease specific measures we have for juvenile idiopathic arthritis (JIA) the classic rheumatologic examination with the evaluation of the number of joints with swelling, pain and limitation on motion as well as the number of active joints, and for damage the Juvenile Arthritis Damage Index (JADI). For juvenile dermatomyositis (JDM) the evaluation of muscle strength through the Childhood Myositis Assessment Scale (CMAS) or the Manual Muscle Testing (MMT), the evaluation of disease activity through the Disease Activity Score (DAS) or the Myositis Disease Activity Assessment Tool (MDAA), and for damage the Myositis Damage Index (MDI). For juvenile systemic lupus erythematosus (JSLE) the evaluation of disease activity through, the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), The Systemic Lupus Activity Measure (SLAM), European Consensus Lupus Activity Measurement (ECLAM) and for damage the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI). Finally there are objective measures or laboratory indicators such as the index of inflammation (ESR or CRP) for JIA, the muscle enzymes for JDM and proteinuria or urine protein/creatinine ration for JSLE. Most of these measures have a correspondent tool to be applied when a child transition to adulthood (for the CHAQ the HAQ, for the CHQ the SF-36) and most are used in the same format for both children and adults. This lecture will describe the current scenario of the measures that could facilitate transition from childhood to adulthood. Disclosure of Interest None Declared

Implementation of clinical trial, observational studies or in general research projects that aim to collect data collection of the health status of patients requires the primary need to obtain a proper approval of the research study from the ethics committee/institutional review board according to European Union (EU) guidelines and nationals laws. In addition participation of the patients elicit the need to obtain a proper consent from the patient. In case of participation of minors the consent must be obtained from the parents with the addition of an assent for children with an appropriate developmental age to understand its content. Until few years ago most of the drugs administered in pediatrics were used off-label but this situation changed recently in Europe with the adoption of a pediatric legislation that facilitate the implementation of clinical trials for new drugs. In addition the EU has adopted directives in order to provide guideline for review by ethics committee and for consent/assent procedures. There is however still a substantial burden to implement clinical studies in children. For example a recent study conducted by the Paediatric Rheumatology International Trials Organisation (PRINTO at www.printo.it) in a rare disease such as juvenile dermatomyositis (JDM) with off label drugs used in current clinical practice worldwide has required activation of 103 clinical centers to enroll 130 patients and the ethical process required by review boards took two years. Of note 97% of the ethical review boards gave their approval without requesting any change at all. Procedures should be implemented at a European level to facilitate implementation and conduct of studies in children by simplifying the bureaucratic burden that is now placed on research in children. Disclosure of Interest None Declared

Systemic juvenile idiopathic arthritis (JIA), also known as Still’s disease, is the most severe category within the group of chronic childhood arthritis which are grouped under the umbrella term of JIA. Systemic JIA has been considered a therapeutic orphan until few years ago when the disease was treated primarily with corticosteroids with the known side effect especially on child growth. More recently the availability of new treatment modalities with biologic agents such as anti IL 6 (tocilizumab) and anti IL1 (anakinra, rilonacept and canakinumab) therapies have greatly advanced the possibilities for these children to be adequately treated. Two trials have been recently completed one with tocilizumab and the other with canakinumab. In the first trial, 112 children with systemic JIA with or without fever were randomized to receive tocilizumab (8 mg/kg every 2 weeks for children over 30 kg of body weight and 12 mg/kg every 2 weeks for children below 30 kg intravenously) or placebo for 3 months followed by an open label extension. After 3 months there was a clear discrimination between tocilizumab and placebo and at the end of year 1 80% of the patients reached at least 70% JIA ACR improvement with 52% able to discontinue corticosteroids. Adverse event were mainly infections and laboratory abnormalities such as neutropenia and aminotransferase elevation. A total of 6 deaths occurred, (3 during the conduct of the study and 3 after). There were also two canakinumab trials administered at a dose of 4 mg/kg/monthly subcutaneously. The first was a single dose double blind placebo controlled trial for 84 patients with fever at enrollment showing that up to 61% of the patients reached at least a JIA ACR 70 response already at day 15. The second Phase III trial was a classic withdrawal study design in which, after 32 weeks of open-label treatment with canakinumab, 100/177 patients who had at least a JIA ACR 30 response and underwent corticosteroid tapering were randomly assigned to continued treatment with canakinumab or to placebo in a double blind fashion until flared occurred. In the withdrawal part the risk of flare was 26% of patients in the canakinumab group versus 75% in the placebo group with corticosteroids discontinuation in 42/128 patients (33%). There were 7 cases of MAS, and infections were more frequent with canakinumab than with placebo. A total of 4 deaths occurred (2 during the trial and 2 after canakinumab discontinuation). This lecture will describe the most recent evidence for the treatment of systemic JIA. Disclosure of Interest None Declared