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The genetic interferonopathies are a heterogeneous group of disorders thought to be caused by the dysregulated expression of interferons and are now commonly considered in the differential diagnosis of children presenting with recurrent or persistent inflammatory phenotypes. With emerging therapeutic options, recognition of these disorders is increasingly important, and neuroimaging plays a vital role. In this article, we discuss the wide spectrum of neuroradiologic features associated with monogenic interferonopathies by reviewing the literature and illustrate these with cases from our institutions. These cases include intracerebral calcifications, white matter T2 hyperintensities, deep WM cysts, cerebral atrophy, large cerebral artery disease, bilateral striatal necrosis, and masslike lesions. A better understanding of the breadth of the neuroimaging phenotypes in conjunction with clinical and laboratory findings will enable earlier diagnosis and direct therapeutic strategies.

BackgroundJuvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1 000 000 children (1). In adult patients there are significant differences between the clinical presentation of diffuse and limited subtypes (2). We reviewed clinical differences in presentation of subtypes in patients in the juvenile systemic scleroderma inception cohort up to 2021.ObjectivesTo study the clinical presentation of jSSc patients with diffuse (djSSc) and limited (ljSSc) subtypes.MethodsWe reviewed the clinical baseline characteristics of the patients, who were recruited to the juvenile scleroderma inception cohort (jSScC) (3, 4) till 1st of December 2021. jSScC is a prospective cohort of jSSc patients, who developed the first non-Raynaud´s symptom before the age of 16 years and are under the age of 18 years at the time of inclusion.Results210 patients with jSSc were included in the cohort, 71% (n=162) had diffuse subtype. The median age at onset of Raynaud phenomenon was 10.4 years (7.3 – 12.9) and the median age at the first non-Raynaud symptom was 10.9 years (7.4 – 13.2). Median disease duration was 2.5 years (1 – 4.4) at the time of inclusion. The female/male ratio was significantly lower in the djSSc subtype (3.7:1 versus 5:1, p< -2 z score (20% versus 4%, p=0.003) and decreased joint range of motion (64% versus 46%, p=0.019). Patients with ljSSc had significantly higher rate of cardiac involvement (13% versus 2%, p=0.001).Regarding patient related outcomes djSSc patients had more severe disease, looking at patient reported global disease activity (VAS 0 – 100) (40 versus 25, p=0.039), patient reported global disease damage (VAS 0 – 100) (40 versus 25, p=0.021) and patient reported assessment of ulceration activity (10 versus 0, p=0.044). Regarding physician related outcomes the physician reported global disease activity (VAS 0 – 100) (32 versus 20, pConclusionIn this jSSc cohort, the largest in the world, djSSc patients have a significantly more severe disease than ljSSc patients. Interestingly, we found no differences regarding interstitial lung disease and pulmonary hypertension.References[1]Beukelman T, Xie F, Foeldvari I. Assessing the prevalence of juvenile systemic sclerosis in childhood using administrative claims data from the United States. Journal of Scleroderma and Related Disorders. 2018;3(2):189-90.[2]Dougherty DH, Kwakkenbos L, Carrier ME, Salazar G, Assassi S, Baron M, et al. The Scleroderma Patient-Centered Intervention Network Cohort: baseline clinical features and comparison with other large scleroderma cohorts. Rheumatology (Oxford). 2018;57(9):1623-31.[3]Foeldvari I, Klotsche J, Kasapcopur O, Adrovic A, Terreri MT, Sakamoto AP, et al. Differences sustained between diffuse and limited forms of juvenile systemic sclerosis in expanded international cohort. www.juvenile-scleroderma.com. Arthritis Care Res (Hoboken). 2021.[4]Foeldvari I, Klotsche J, Torok KS, Kasapcopur O, Adrovic A, Stanevica V, et al. CHARACTERISTICS OF THE FIRST 80 PATIENTS AT TIMEPOINT OF FIRST ASSESSMENT INCLUDED IN THE JUVENILE SYSTEMIC SCLEROSIS INCEPTION COHORT. WWW.JUVENILESCLERODERMA.COM. Journal of Scleroderma and Related Disorders. 2018;4(1-13).Disclosure of InterestsNone declared

BackgroundJuvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1 000 000 children (1). The Juvenile Systemic Scleroderma Inception cohort (jSScC) is the largest cohort of jSSc patients in the world. The jSScC collects longitudinal data prospectively in jSSc, allowing the evaluation of the development of organ involvement and patients and physician reported outcomes in jSSc over time.ObjectivesTo review the changes in the clinical characteristics and patient and physician reported outcomes over 12 months observation period from the time of inclusion into the cohort.MethodsThe jSScC cohort enrolls jSSc patients who developed the first non-Raynaud´s symptom before the age of 16 years and are under the age of 18 years at the time of inclusion (2, 3). We reviewed jSScC patient clinical data and patient and physician reported outcomes, who had 12 months follow up from the time of inclusion until 1st of December 2021.ResultsWe could extract data of 113 patients. The female/male ratio was 3.5:1. Median age of onset of Raynaud´s was 10.1 years and the median age of onset of non-Raynaud´s was 10.8 years. Eighty-eight percent of the patients were treated with disease modifying anti-rheumatic drugs (DMARDs) at time of inclusion in the cohort (T0) and 93% after 12 months (T12). Median disease duration was 2.5 years at T0. Antibody profile stayed unchanged. Only 3 clinical parameters changed and improved significantly, the median modified Rodnan skin score improved from 13 to 8 (p=0.002), the number of patients with swollen joints decreased from 17% to 8% (p=0.043) and number of patients with joints with pain on motion decreased from 20% to 12% (p=0.048). All other organ involvement did not show any statistically significant change from T0 to T12.All collected patient reported outcomes improved significantly from T0 to T12: the patient reported disease activity (VAS 0 – 100) from 40 to 20 (p=0.011), the patient reported disease damage (VAS 0 – 100) from 40 to 20 (p=0.001), patient reported ulceration activity (VAS 0 – 100) from 10 to 0 (p=0.02) and the CHAQ score from 0.3 to 0.1 (p=0.002). Two of the three physician reported outcomes improved significantly, the physician global disease activity (VAS 0 – 100) from 30 to 20 (p=0.011) and physician reported global disease damage (VAS 0 – 100) from 30 to 25 (p=0.028).ConclusionSkin and musculoskeletal clinical features improved over 12 months, with almost all patients on DMARDs, supporting likely response of these features to therapy. It was promising that internal organ involvement, like cardiac and lung, although potentially stable, did not significantly worsen or increase. The most striking observation in the positive direction is improvement across several patient and physician reported outcome measures over the 12 month time period in this large international cohort.References[1]Beukelman T, Xie F, Foeldvari I. Assessing the prevalence of juvenile systemic sclerosis in childhood using administrative claims data from the United States. Journal of Scleroderma and Related Disorders. 2018;3(2):189-90.[2]Foeldvari I, Klotsche J, Kasapcopur O, Adrovic A, Terreri MT, Sakamoto AP, et al. Differences sustained between diffuse and limited forms of juvenile systemic sclerosis in expanded international cohort. www.juvenile-scleroderma.com. Arthritis Care Res (Hoboken). 2021.[3]Foeldvari I, Klotsche J, Torok KS, Kasapcopur O, Adrovic A, Stanevica V, et al. CHARACTERISTICS OF THE FIRST 80 PATIENTS AT TIMEPOINT OF FIRST ASSESSMENT INCLUDED IN THE JUVENILE SYSTEMIC SCLEROSIS INCEPTION COHORT. WWW.JUVENILESCLERODERMA.COM. Journal of Scleroderma and Related Disorders. 2018;4(1-13).Disclosure of InterestsNone declared

BackgroundJuvenile systemic scleroderma (jSSc) is an orphan disease with a prevalence of 3 in 1,000,000 children. Currently no medications are licensed for the treatment of jSSc. Due to its rarity, only recently have the first management and treatment guidelines been published, the jSSc SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) recommendations, reflecting consensus opinion upon pediatric rheumatologists (1).ObjectivesTo better understand treatment practices internationally for jSSc, both at baseline and over 24 months observation period and to compare if real world therapies are congruent with the recent SHARE recommendations.MethodsThe juvenile systemic sclerosis inceptions cohort (jSScC) is a multinational cohort that prospectively collects clinical data, including medications at baseline and subsequent visits. The jSScC enrollment criteria include age of onset of the first non-Raynaud symptom younger than 16 years and age younger than 18 years at cohort entrance. The frequency of medications (general category and specific medication) was calculated across the cohort at timepoint 0 (enrollment), 12 months and 24 months.ResultsWe extracted data from the jSScC of patients who were followed for 12 or 24 months. 109 patients were followed at time point 0 (T0) and 12 months (T12), and data was available for 77 of them up at 24 months (T24). The mean age of the patients was 13.2 years at the timepoint 0. 77% were female and 75% had diffuse subtype. Disease duration at baseline visit was 3.1 years. The medications the patients were on recorded by the physician were captured at T0, T12 and T24 listed in Table 1.Table 1.MEDICATIONSTime point 0N=109T12 monthsN=109T24 months N=77Any Medication92% (100)97% (106)97% (75)Vascular medications Endothelial receptor antagonist16% (17)24% (26)21% (16) PDE-5-Blocker5% (5)8% (9)9% (7)ImmunomodulatorsCorticosteroids52% (57)44% (48)44% (21)All csDMARDs:81% (88)93% (101)92% (71) csDMARDs monotherapy61% (67)66% (72)60% (46) csDMARDs combination therapy17% (18)15% (16)14% (11) Methotrexate51% (56)50% (55)39% (30) Mycophenolate Mofetil26% (28)44% (48)47% (36) Hydroxychloriquine11% (12)15% (16)21% (16) Cyclophosphamide12% (13)2% (2)1% (1) Azathioprine2% (2)2% (2)3% (2)All bDMARDs:5% (5)14% (15)18% (14) bDMARDs monotherapy2%(2)2%(2)1% (1) bDMARDs combined with csDMARDs3% (3)12% (13)17% (13) Tocilizumab2% (2)10% (11)14% (11) Rituximab2% (2)4% (4)4% (3) Adalimumab1% (1)0% (0)0% (0)Autologous Stem cell transplantation0% (0)1% (1)0% (0)csDMARDs: Conventional synthetic disease-modifying antirheumatic drugsb DMARDs: Biological disease-modifying antirheumatic drugsConclusionAt baseline half of the patients were on corticosteroids. This is more frequent than typical adult SSc practice but coincides with jSSc SHARE treatment recommendations (#1). After 12 months observation in the cohort over 90% of patients received a DMARD therapy. Methotrexate and mycophenolate mofetil were the most commonly prescribed DMARDs, which also reflects the SHARE treatment recommendations (#2, #3). At 12 months the use of glucocorticoid decreased and the use of bDMARDs increased. In general, biological DMARDs are typically considered in severe or refractory (SHARE recommendation #7), reflecting the lower percentage compared to csDMARDs. Autologous stem cell transplantation was observed in one patient at 12 months, reflecting an option in jSSc with progressive and refractory disease (SHARE recommendation #8). Endothelial receptor antagonists, such as bosentan, were used over time in approximately 20% of the patients, reflecting SHARE recommendation #6 for pulmonary hypertension and/or digital tip ulcers. This is the first evaluation looking at clinical medication practice pattern in jSSc, and its comparison to recently published consensus guidelines.References[1]Foeldvari I, Culpo R, Sperotto F et al. Consensus-based recommendations for the management of juvenile systemic sclerosis. Rheumatology (Oxford). 2021;60(4):1651-8.Disclosure of InterestsNone declared

BackgroundJuvenile systemic sclerosis (jSSc) is an orphan autoimmune disease with a prevalence of 3 in 1 000 000 children. Information on long-term development of organ involvement and clinical characteristics of jSSc patients in adulthood are lacking. It was believed that patients in adult cohorts may represent a survival biased population.ObjectivesTo assess differences in clinical characteristics of jSSc-onset patients from the pediatric age group, with a mean disease duration of 3 years, compared to the adult age jSSc-onset group, with a mean disease duration of 18.5 years.MethodsWe extracted clinical data at time of inclusion into the cohorts from the Juvenile Scleroderma Inception Cohort (jSScC) and data from juvenile-onset adult SSc patients from the European Trials and Research Group (EUSTAR) cohort. We compared the clinical characteristics of the patients by descriptive statistics.ResultsWe extracted data of 187 jSSc patients from the jSScC and 236 patients from EUSTAR. The mean age at time of assessment was 13.4 years old in the jSScC and 32.4 years old in EUSTAR. The mean disease duration since first non-Raynaud was 3.0 years in jSScC and 18.5 years in the EUSTAR (Table 1).We found significant differences between the cohorts. There were more female patients in EUSTAR (87.7% versus 80.2%, p=0.04). More patients had diffuse subtype in jSScC (72.2% versus 40%, pTable 1.Clinical characteristics of juvenile onset SSc patients at time point of the inclusion into the juvenile scleroderma inception (jSScC) cohort and in the adult EUSTAR- cohortjSScCEUSTAR CohortP valueNumber of patients1872360.04Age in years, mean (SD)13.4 (3.6)32.4 (15.4)Female patients, n (%)150 (80.2%)207 (87.7%)jSSC Subtype, n (%)diffuse135 (72.2%)87 (38.1%)limited52 (27.8%)121 (53.3%)Age at Raynaud onset in years, mean (SD)10.0 (3.9)13.7 (9.1)Age at non-Raynaud onset in years, mean (SD)10.3 (3.9)11.7 (3.7)Duration since first Raynaud symptoms in years, mean (SD)3.4 (2.7)20.6 (15.9)Duration since first non-Raynaud symptoms in years, mean (SD)3.0 (2.7)18.5 (15.6)Raynaud´s, n (%)170 (90.9%)222 (94.9%)ANA positive, n (%)166 (91.7%)210 (92.9%)0.99Anti-Scl 70 positive, n (%)62 (34.4%)73 (33.3%)0.68Modified Rodnan Skin Score, mean (SD)5%Data missingModified Rodnan Skin Score, mean (SD)14.2 (11.7)12.1 (14.5)0.02Digital ulceration, n (%)At the time of inclusion33 (17.8)21 (26.6%)0.01In the past history100 (54.1%)34 (43%)Telangiectasia62 (37.4%)42 (53.2%)0.04FVC, mean (SD)84.1 (18.6)84 (22.4)0.96DLCO, mean (SD)75.4 (19.2)86.3 (19.9)Arterial hypertension, n (%)10 (5.4%)20 (8.5%)0.26Renal crisis, n (%)03 (1.3%)0.26Esophageal involvement, n (%)63 (33.7%)149 (63.7%)Intestinal involvement, n (%)62 (33.2%)56 (23.8%)0.04Articular involvement, n (%)34 (18.3%)27 (11.6%)0.06Muscular involvement, n (%)31 (19.3%)46 (19.8%)0.45ConclusionPatients with jSSc-onset who are currently adult age (defined as >18 years of age) are less frequently male and from the diffuse subset, have lower mRSS, less digital ulcers and intestinal involvement. This might represent a combination of both survival bias and/or be explained by the longer observation time with less active disease (i.e. natural progression decreased mRSS over time). Further long-term observational studies with jSSc patients are required to address this issue.Disclosure of InterestsNone declared

BackgroundMAS is a severe, life-threatening complication of rheumatic diseases that occurs most frequently in patients with sJIA. The mainstay of treatment for MAS is high dose glucocorticoids (GCs); however, GCs do not provide adequate control in all patients. Additional treatments are used without a standardized approach; however, morbidity and mortality remain high. Data from animal models of MAS and from observational studies in patients suggest that overproduction of IFNγ is a driver of the hyperinflammation observed in MAS; neutralization of IFNγ has been shown to revert the signs and symptoms of MAS in murine models, and high IFNγ levels are strongly correlated with laboratory parameters of disease severity in patients.ObjectivesTo assess the efficacy and safety of intravenous (IV) infusions of emapalumab, a fully human, anti-IFNγ monoclonal antibody, in patients with MAS in sJIA.MethodsOpen-label, single-arm, phase 2 study (NCT03311854) that included patients with MAS (2016 ACR/EULAR criteria) in sJIA who had failed high-dose IV GCs and other treatments. Emapalumab was initiated at a dose of 6 mg/kg on Day 0 and continued at 3 mg/kg every 3 days until Day 15, and then twice weekly until Day 28 to ensure rapid and complete IFNγ neutralization after initiating treatment. As per protocol, 10 infusions were planned over the 4 weeks; however, treatment could be shortened if MAS remission was achieved earlier, or extended if required to achieve remission. Complete response (CR) was defined as resolution of clinical signs and symptoms of MAS according to the investigator, and normalization of laboratory parameters relevant to MAS. All patients were followed up for 4 weeks after the last infusion of emapalumab and offered to enter a 1-year, follow-up study (NCT02069899).ResultsFourteen patients (10 females) were enrolled (11 in Europe, 3 in the USA). Several patients had previously received cyclosporine A and/or anakinra, in addition to high-dose GCs. Six patients received emapalumab until Day 28. Seven patients discontinued emapalumab early due to MAS remission (as per investigator’s assessment); one patient received treatment up to Day 38. Emapalumab treatment rapidly neutralized IFNγ, as documented by CXCL9 levels. A CR was achieved by 13/14 patients during the study. One patient stopped emapalumab after 3 doses because of achievement of MAS remission as per investigator’s assessment, but lactate dehydrogenase levels remained >1.5× upper limit of normal. At Week 8, 11/14 patients had a CR; 2 achieved a CR during the study, but not at Week 8, because of a single laboratory parameter abnormality in each patient. Overall, all measured laboratory parameters related to MAS activity rapidly improved with emapalumab treatment. GCs were tapered in all patients by Week 8 (≥50% reduction, n=12; GC dose ≤1 mg/kg/day, n=8). Administration of anakinra for the treatment of underlying sJIA was maintained/introduced during the study, as required. No patients discontinued treatment for safety reasons. One treatment-related serious adverse event was reported (cytomegalovirus reactivation that resolved with antiviral treatment). All patients entered the long-term, follow-up study and were alive at last visit.ConclusionEmapalumab administration led to rapid IFNγ neutralization, was efficacious in controlling MAS in all patients, and was well tolerated with a favorable safety profile. These results support the pathogenic role of IFNγ in MAS in sJIA and the therapeutic value of IFNγ neutralization in MAS patients who have failed high-dose GCs.Disclosure of InterestsFabrizio De Benedetti Consultant of: Sobi, AbbVie, Pfizer, Roche, Sanofi, Novartis, Novimmune, Grant/research support from: Sobi, AbbVie, Pfizer, Roche, Sanofi, Novartis, Novimmune, Alexei Grom Consultant of: Novartis, AB2 Bio, Paul Brogan Consultant of: Sobi, Novartis, Roche, UCB, Claudia Bracaglia: None declared, Manuela Pardeo: None declared, Giulia Marucci: None declared, Despina Eleftheriou Speakers bureau: Sobi, Charalampia Papadopoulou Speakers bureau: Sobi, Pierre Quartier Speakers bureau: Sobi, AbbVie, Chugai-Roche, Lilly, Novartis, Pfizer, Consultant of: Sobi, AbbVie, Chugai-Roche, Lilly, Novartis, Pfizer, Jordi Anton Consultant of: Sobi, Novartis, Roche, Pfizer, AbbVie, GSK, Rikke Frederiksen Employee of: Sobi, Veronica Asnaghi Employee of: Sobi, Cristina de Min Consultant of: Sobi

Supplemental Material for Aquaporin-4 IgG antibody-related disorders in patients with juvenile systemic lupus erythematosus by E Moraitis, Y Stathopoulos, Y Hong, M Al-Obaidi, K Mankad, Y Hacohen, D Sen, C Hemingway and D Eleftheriou in Lupus

Thrombosis is common in Behçet's Syndrome (BS), and there is a need for better biomarkers for risk assessment. As microparticles expressing Tissue Factor (TF) can contribute to thrombosis in preclinical models, we investigated whether plasma microparticles expressing Tissue Factor (TF) are increased in BS. We compared blood plasma from 72 healthy controls with that from 88 BS patients (21 with a history of thrombosis (Th+) and 67 without (Thâ '). Using flow cytometry, we found that the total plasma MP numbers were increased in BS compared to HC, as were MPs expressing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p 0.7 had a history of clinical thrombosis. We conclude that TF-expressing MP are increased in BS and that an imbalance between microparticulate TF and TFPI may predispose to thrombosis.

Thrombosis is common in Behçet’s Syndrome (BS), and there is a need for better biomarkers for risk assessment. As microparticles expressing Tissue Factor (TF) can contribute to thrombosis in preclinical models, we investigated whether plasma microparticles expressing Tissue Factor (TF) are increased in BS. We compared blood plasma from 72 healthy controls with that from 88 BS patients (21 with a history of thrombosis (Th+) and 67 without (Th−). Using flow cytometry, we found that the total plasma MP numbers were increased in BS compared to HC, as were MPs expressing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p 0.7 had a history of clinical thrombosis. We conclude that TF-expressing MP are increased in BS and that an imbalance between microparticulate TF and TFPI may predispose to thrombosis.

Background This study explores young people’s daily experiences of living with Juvenile Idiopathic Arthritis (JIA) and their thoughts, beliefs and feelings related to the biological drug Etanercept, prescribed as part of their treatment. Methods An Interpretive Phenomenological approach was used to allow in-depth examinations of the young people’s personal accounts of their lived experiences. Data were obtained from 6 young people between the ages of 10–13 years, from one tertiary institution’s Paediatric Rheumatology department using audio-taped open-ended interviews. Results The transcripts yielded seven thousand words of data and two hundred significant statements, which were reduced to five themes; 1) Who understands me, 2) Medicines and injections, 3) Challenges of schooling and friendships, 4) Being different, and 5) Exclusion from sports. There were marked similarities between the young people’s statements; however, there were also some striking differences. The theme ‘Who understands me’ yielded the biggest section of data, but also produced the biggest disparity between the young people. Two patients were very clear that they thought everyone ‘understands’, whilst two other patients held the belief that ‘no one understood’. This paper explores these statements in further detail. Conclusions The findings from this study can give healthcare professionals novel insight into the likely reactions to-treatment for JIA and, through this, enable them to offer improved support, education and early intervention before these issues become a concern. This study also provides insight into the emotional resilience of young people with JIA. Electronic supplementary material The online version of this article (doi:10.1186/s12969-016-0083-7) contains supplementary material, which is available to authorized users.

Demographics of all patients captured at time of interview to provide the reader with more clarity of the cohort enrolled on this study. The table shows the data collected such as medications and disease activity at time of interview. (DOC 37Â kb)

The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at ∈ European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better fu treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine ‘sections’ in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients. © 2016 Ferrata Storti Foundation.

Microscopic polyangiitis (MPA) is a systemic small vessel vasculitis that is included in the pulmonary-renal syndromes. Although glomerulonephritis represents the major clinical feature of MPA indicative of renal involvement, diffuse alveolar haemorrhage is the classic manifestation of pulmonary involvement. However, pulmonary fibrosis is a less frequently reported pulmonary manifestation. Herein we describe a patient who was diagnosed with MPA presenting with radiographic evidence of pulmonary interstitial fibrosis as an early clinical manifestation accompanied by constitutional symptoms such as fever and weight loss. We also include a short literature review focusing on the association between pulmonary fibrosis and MPA.

Background Monogenic autoinflammatory diseases (AID) are severe lifelong systemic inflammatory disorders with dysregulated innate immunity, causing significant morbidity, mortality, and economic burden. The number of AID is rapidly expanding. Securing a molecular diagnosis is of major importance for treatment, prognosis, and genetic counselling. Routine genetic screening is time-consuming, costly, and lacks sensitivity since only common disease harbouring exons of a minority of the known AID genes are currently tested using Sanger sequencing. Next-generation sequencing (NGS) offers the ability to rapidly and cost-effectively screen all exons of a gene panel containing hundreds of genes. This approach has not yet been routinely introduced in the UK for AID. Objectives To develop and evaluate the performance of a NGS gene panel for AID. Methods The Agilent SureDesign tool was used to design an NGS panel targeting 113 genes, grouped into 9 broad clinical phenotypes: AID; monogenic vasculitis/vasculopathy; complement defects; monogenic lupus; hemophagocytic lymphohistiocytosis (HLH); early-onset inflammatory bowel disease; autoimmune lymphoproliferative syndromes; monogenic stroke; and hereditary amyloidosis. The targeted region includes coding exons, conserved non-coding exons, upstream promoter regions, and splice sites. Captured and indexed libraries (QXT Target Enrichment System) were sequenced as a multiplex of 16 samples on an Illumina MiSeq sequencer in paired-end mode. Positive controls for panel validation comprised 19 DNA samples from patients with confirmed mutations in a variety of genes on the panel. We then applied the panel to test 29 prospective samples with suspected but unconfirmed monogenic inflammation. Read alignment, variant calling, and annotation were performed using Agilent SureCall v3.0 software. Results In the validation stage, our targeted panel detected all known mutations in the 19 positive control samples with an average read depth of 244X (+/− 29X) across the captured genes. The panel was effective at detecting different types of variants, including rare and common single nucleotide variants (SNVs), insertion/deletions, splice-junction variants, upstream promoter region variants, and somatic mosaicism. Prospective testing of the panel in 29 patients revealed potential pathogenic variants in 14 of the 29 patients giving a detection rate of 48%. These included atypical patients with novel mutations in specific exons/genes, not currently routinely available for testing by Sanger sequencing in the NHS. Conclusions This study demonstrates the clinical utility of a comprehensive NGS-based targeted gene panel which was both highly sensitive and specific in detecting different sequence variants of clinical significance. We are currently integrating this panel into a routine diagnostic laboratory testing strategy for monogenic inflammation. This will facilitate accurate and timely molecular diagnosis, more targeted treatment, and ultimately better outcomes for our patients. Acknowledgement This work was supported by Rosetrees Trust and Swedish Orphan Biovitrum (SOBI). Disclosure of Interest None declared

*Department of Paediatric Rheumatology, Institute of Child Health, London; and Infectious Diseases and Microbiology Unit, Institute of ChildHealth, London, UKTo cite this article: Eleftheriou D, Hong Y, Klein NJ, Brogan PA. Thromboembolic disease in systemic vasculitis is associated with enhancedmicroparticle-mediated thrombin generation. J Thromb Haemost 2011; 9: 1864–7.

Ischaemic stroke (arterial ischaemic stroke and cerebral sinovenous thrombosis) is increasingly recognised in childhood and has a significant attendant morbidity and mortality.To review the most recent evidence underpinning treatment of childhood ischaemic stroke.A literature search was performed through Medline and Cochrane Reviews database using search terms such as management/treatment/therapy of ischaemic stroke in children, anticoagulants, thrombolysis, aspirin for the prevention of stroke in childhood. Articles reviewed were published within the last 20 years.Two separate treatment guidelines for childhood ischaemic stroke have been published and are those of the Royal College of Physicians in the UK and more recently the American Heart Association Stroke Council. In addition, the American College of Chest Physicians provide guidance on the use of anticoagulants and antithrombotic therapy in childhood stroke. Supportive care and neuroprotective strategies are important considerations in children with ischaemic stroke. Antithrombotic strategies are advocated; the choice of agent varies according to the underlying risk factors. Divergence between the published guidelines highlights the lack of a firm evidence base for published recommendations. Thrombolytic treatment is not advocated. Specific pathologies may require targeted management, for example surgical revascularisation for moyamoya. Clinical trials are urgently needed to establish comprehensive evidence-based guidelines for the treatment of childhood ischaemic stroke.

Background: Circulating endothelial cells (CECs) are biomarkers for endothelial cell (EC) injury and are quantified using immunomagnetic bead extraction (IBE), or flow cytometry (FC). Reports suggest that there is good agreement between these methods for CEC quantification. Objectives: We examined levels of agreement between these techniques in children with systemic vasculitis. Methods: We addedHUVECorhuman pulmonary arteryECto whole blood to optimize FC gating strategies for EC. EC-optimized FC was then compared with IBE for CEC enumeration in 25 children with vasculitis and 20 healthy controls. Results: Using Bland– Altman analysis, agreement between IBE and EC-optimized FC was poor in children with vasculitis (n = 25) and healthy controls (n = 20): IBE consistently detected higher values than the EC-optimized FC method: themean difference between the two techniques was 60 CECs mL)1, 95% CI ±374 CECs mL)1 (paired analyses of 45 individuals). Agreement was poorest for vasculitis patients:mean difference (IBE – EC-optimized FC) 120 CECs mL)1, 95% CI ±460 CECs mL)1 (P = 0.018). We identified three reasons for this discrepancy: (i) sub-optimal FC gating parameters previously used for detecting CECs; (ii) inherent lack of sensitivity of FC compared with IBE for CEC rare event detection; and (iii) use of lysis buffers required for FC causing CEC lysis. Conclusions: There was poor agreement between EC-optimized FC and IBE for the quantification of CECs from children with active vasculitis and controls.We emphasize that in this clinical setting the two techniques are not directly comparable when comparing results obtained using these different methodologies.

Background Juvenile systemic sclerosis (jSSc) is an orphan autoimmune disease. Several publications in adults looked at the differences between limited and diffuse subtypes. There is rarity of data regarding this topic in pediatric jSSc. The juvenile scleroderma inception cohort (www.juvenilescleroderma.com) is a prospective standardized register for patients with jSSc. Objectives Comparison of features of patients with limited jSSc (ljSSc) and diffuse jSSc (djSSc) subtypes at the time of inclusion in the registry Methods Patients with jSSc were included worldwide into the juvenile scleroderma inception cohort. We compared the demographics and clinical features of the ljSSc and djSSc. Results Up till now 39 patients were enrolled, 29 with djSSc and 10 with ljSSc. 5 in the diffuse (17%) and 3 in the limited subtype (30%) had an overlap feature. The mean follow up of the patients in the cohort was 6.4 years in the djSSc and 5.3 years in ljSSc. 76% in the djSSc and 80% in the ljSSc group were female. The mean age at the onset of Raynaud9s Phenomenon was 8.7 years in the jdSSc and 12.9 years in ljSSc group while the mean age at the onset of the first non-Raynaud presentation was 9.1years in djSSc and 13.8 years ljSSc. At the time of the inclusion the mean modified Rodnan Skin Score was 19.6 in the djSSc and 7.5 in ljSSc. 70% of patients in both groups had already capillary changes, but 67% in djSSc and only 33% in ljSSc had already history of ulcerations and 32.1% presented with active ulceration in the djSSc and none in the ljSSc. 72% of djSSc and 50% of ljSSc had cardiopulmonary involvement. The two patients with pulmonary hypertension had djSSc. 27.5% in djSSc and 30% in ljSSc group showed signs of interstitial lung disease on imaging. All 3 patients with renal involvement had djSSc. In both groups 30% had gastrointestinal involvement. Around 80% had musculoskeletal involvement in both subtypes. Anti-Scl 70 positivity was found in 40% of djSSc and 37.5% in ljSSc. Only 1 patient in the djSSc group had anticentromere antibody. Conclusions We present the data on the first 39 patients with jSSc included in our cohort. Patients with djSSc and ljSSc differ in several characteristics. Patients with djSSc were younger at onset, had more often capillary changes and active ulcerations, pulmonary hypertension and renal involvement. The characteristics of the pediatric subtypes differs from adults with SSc. Disclosure of Interest None declared

2.75±0.14, P = 0.11). Dysbiosis was observed in all CD patients prior to therapy. EEN therapy had a positive effect in all patients, with 80% going into remission. In some patients, the positive effect diminished following the conclusion of EEN therapy. Significantly, the number of operational taxonomic units (OTU) decreased dramatically upon starting EEN and this corresponded with CD remission. Recurrence of CD corresponded with an increase in OTUs. Six families within Firmicutes were found to behave consistently during and following EEN therapy, frequently correlating with disease activity, a finding confirmed by whole genome HTS. Our results demonstrate that EEN leads to common and patientspecific alterations in the microbiota of CD patients, a number of which correlate with disease activity.

We present the case of a young adult with type I Arnold-Chiari malformation (AMC1) and syringomyelia who developed central sleep apnoea and chronic respiratory failure, successfully treated with nocturnal noninvasive positive pressure ventilation ventilation (NIPPV). An extensive syringomyelic cavity (from bulbar to L4 segment) with severe impairment of the IX cranial nerve was documented and remains, although reduced, after the neurosurgical treatment. At baseline evaluation, the patient showed a moderate restrictive ventilatory defect, severe hypercapnic respiratory failure, abnormal control of breathing characterized by the absence of response to hypoxia and hypercapnia, and severe nocturnal central apnoeas. Nocturnal NIPPV was then started in the A/C mode with an improvement in blood gas values. Further evaluations were performed 10 and 18 months later. A progressive significant improvement of lung volumes, both in sitting and supine position, associated with a slight improvement of blood-gas values were observed. Nonetheless, the breathing pattern abnormalities persisted. Polysomnographic evaluation during mechanical ventilation showed a normalization of breathing pattern with arterial oxygen saturation (SaO2)90% throughout the night.

Background Primary angiitis of the central nervous system in children (cPACNS) is an inflammatory vasculitis that solely affects the CNS vessels in the absence of a systemic inflammatory process. Circulating endothelial cells (CECs) are increasingly described as biomarkers for tracking vascular injury [1]. Additionally, bone marrow-derived endothelial progenitor cells (EPCs) are thought to play a pivotal role in the regeneration of damaged endothelium. We describe the relationship of CECs and EPCs to clinical and/or radiological disease progression in cPACNS.

CAPS is caused by mutations in the NLRP3 gene and is inherited in an autosomal dominant fashion. About 40% of children with CINCA are mutation negative by conventional Sanger sequencing, but NLRP3 somatic mosaicism can be identified by sensitive multi-parallel sequencing (MPS) in a significant proportion of such patients.