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BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Introduction/Background MDA5-positive juvenile dermatomyositis (JDM) represents a distinct clinical phenotype associated with skin and oral ulceration, milder muscle involvement and a higher incidence of interstitial lung disease (ILD) and severe rapidly progressive ILD (RP-ILD). Description/Method The objectives were to describe the presenting clinical characteristics of patients with MDA5-positive JDM, the incidence of ILD and risk factors associated with development of RP-ILD. Retrospective clinical notes review of patients with MDA5-positive JDM managed at Great Ormond Street Hospital (GOSH) over a 24-year period. Discussion/Results Demographics Twenty-five patients were managed at our centre with MDA5-positive JDM. One additional patient was excluded as no notes available. Sixty-four % females. Sixty % were White British, 20% Black African, 8% Mixed, 8% Asian, 8% European and 4% South Asian. Median age of presentation was 10.0 years (IQR 6.9,12.3). Diagnostic delay was significant, with median 14 weeks (8,26) between initial symptoms and diagnosis. 24% of this cohort were also Ro-52 positive. Presentation: All patients had skin involvement; 52% ulcerating skin disease, 64% heliotrope rash and 100% Gottrons papules on initial presentation. Forty-four % had peri-ungal changes, 35% digital pitting/infarcts and 64% nailfold changes. 40% had peri-orbital oedema. Muscle involvement was present in all, with median CMAS 40/52 (36,44) and MMT8 57/80 (51,62). Eighty-eight % had arthritis; initial active joint count was available for 16 patients with median 5.5 joints (3,16). 40% had gastrointestinal symptoms; fever, weight loss and mouth ulcers were present in 52%, 52% and 60% respectively. Twenty-four % had respiratory symptoms at diagnosis. Interstitial lung disease: 52% were diagnosed with ILD and a further 20% had abnormal pulmonary CT scans not thought to be diagnostic of ILD. 13% (2 patients) had RP-ILD; both of whom died despite immunosuppression and extracorporeal membrane oxygenation. There were no other deaths amongst this cohort. No respiratory involvement was identified in 28%. Of 19 patients who had a CT chest at diagnosis, 84% were abnormal. Only 1 patient developed respiratory involvement during disease course whilst on treatment; the other 93% with ILD had evidence of ILD at diagnosis. Out of 58 putative variables, 4 risk factors were associated with development of RP-ILD which reached statistical significance, a further 3 factors were significantly protective, as is shown in Table 1. 2 patients had pneumocystis pneumonia (PCP), both of whom required intensive care and one associated with death. Key learning points/Conclusion Skin and muscle involvement were identified in all patients, with the majority also presenting with ulcerating skin disease, oral ulceration and arthritis. The majority of this cohort had lung involvement and 2 patients died of RP-ILD. Four risk factors were found to be predictive of RP-ILD and a further 3 protective factors were identified. Rapid deterioration of respiratory symptoms was associated with PCP, while ILD was unlikely to develop whilst on treatment if not present at diagnosis. These findings need to be validated in a larger cohort of patients.

Introduction/Background Chronic Recurrent Multifocal Osteomyelitis (CRMO), also known as chronic nonbacterial osteomyelitis (CNO), is a rare autoinflammatory condition affecting the bones. It occurs primarily in children and teenagers and is characterised by bone pain and swelling in the absence of infection or tumour. The incidence of CRMO remains uncertain, with estimates ranging from 0.4-1 per 100,000 person years. Description/Method The primary aim of the study was to identify the incidence of CRMO in patients under the age of 16 in the United Kingdom (UK) and Republic of Ireland (ROI). Additional aims include describing the demographics, clinical features, treatment, and healthcare needs of patients with CRMO. A prospective surveillance study was undertaken via the British Paediatric Surveillance Unit. A monthly e-reporting card was sent to all registered paediatric consultants in the UK and ROI. A parallel surveillance study was sent via the British Society for Children’s Orthopaedics to identify patients managed solely by orthopaedics. A standardised questionnaire was sent to the reporting clinicians to collect further information. Discussion/Results During initial 13 months of surveillance, 168 cases were reported. 23 questionnaires were not returned (13.7% of reported cases). After de-duplication, and removal of cases outside the reporting time period and age-group, 82 confirmed and 8 probable cases were included in these interim results. The estimated incidence of CRMO is 0.605 cases/100,000 children per year. Median age at time of diagnosis was 10 years (range 3-16). 53 (58.9%) of cases were female. Median delay from symptom onset to diagnosis was 5 months and 16 patients (17.78%) had a delay of greater than 12 months. Most (48.9%) of the cases were diagnosed by paediatric rheumatology specialists. Other cases were diagnosed by orthopaedics (16.7%), general paediatricians (15.6%) or by a multidisciplinary team. 34 cases (37.8%) reported requiring hospital admission related to CRMO. The most common presenting feature was bone pain (96.67%). 34 patients (37.8%) presented with clavicular pain, and thirty-one (34.4%) had unifocal bone pain. Patients also presented with bone swelling (52.2%), joint swelling (20.0%), fever (12.2%) and general malaise (13.3%). A median of 3 radiological investigations were reported for each case, of which 61 (67.7%) cases had whole body MRI performed. Additionally, 33 cases (36.67%) had bone biopsy. At initial reporting, the most common treatment was NSAIDs (90.0%) and bisphosphonates (33.3%). Key learning points/Conclusion Our results estimate the incidence of CRMO as 0.605 cases per 100,000 person years. The study will continue to capture new CRMO cases for a further 12 months. Reported cases will be followed up for 24 months. This prospective study of all incident cases of CRMO within the UK and ROI will provide insight into the medium-term outcomes and treatment strategies used by clinicians. These results will provide a valuable baseline for further research and improvement in care for patients with CRMO.

Objectives Uncertainty around clinical heterogeneity and outcomes for patients with JDM represents a major burden of disease and a challenge for clinical management. We sought to identify novel classes of patients having similar temporal patterns in disease activity and relate them to baseline clinical features. Methods Data were obtained for n = 519 patients, including baseline demographic and clinical features, baseline and follow-up records of physician’s global assessment of disease (PGA), and skin disease activity (modified DAS). Growth mixture models (GMMs) were fitted to identify classes of patients with similar trajectories of these variables. Baseline predictors of class membership were identified using Lasso regression. Results GMM analysis of PGA identified two classes of patients. Patients in class 1 (89%) tended to improve, while patients in class 2 (11%) had more persistent disease. Lasso regression identified abnormal respiration, lipodystrophy and time since diagnosis as baseline predictors of class 2 membership, with estimated odds ratios, controlling for the other two variables, of 1.91 for presence of abnormal respiration, 1.92 for lipodystrophy and 1.32 for time since diagnosis. GMM analysis of modified DAS identified three classes of patients. Patients in classes 1 (16%) and 2 (12%) had higher levels of modified DAS at diagnosis that improved or remained high, respectively. Patients in class 3 (72%) began with lower DAS levels that improved more quickly. Higher proportions of patients in PGA class 2 were in DAS class 2 (19%, compared with 16 and 10%). Conclusion GMM analysis identified novel JDM phenotypes based on longitudinal PGA and modified DAS.

ObjectiveTo describe the phenotype, disease course, and treatment of a large cohort of children with sarcoidosis.MethodsPatients with biopsies consistent with sarcoidosis, performed between 2010 and 2020, were included in this study. Patients' notes were reviewed retrospectively. Children with disease onset before 5 years of age were compared with older children. Regression analysis was performed to determine predictors of treatment outcome.ResultsIn total, 48 children with a mean age at diagnosis of 9.5 years, with a male to female ratio of 0.71, were identified. In total, 72% of the children were of Black race and 94% had multiorgan disease, with an average of 4.8 organs involved, most commonly lymph nodes (65%), skin (63%), and eyes (60%). Laboratory findings of note included raised serum calcium in 23% of patients and raised angiotensin-converting enzyme in 76% of patients. Out of 14 patients tested, 6 had mutations in NOD2. In total, 81% of patients received systemic steroids and 90% received conventional disease-modifying antirheumatic drugs (DMARDs); in 25% of patients, a biologic was added, mostly anti–tumor necrosis factor (anti-TNF). Although most patients could be weaned off steroids (58%), most remained on long-term DMARDs (85%). Children under the age of 5 years presented more often with splenomegaly (P= 0.001), spleen involvement (P= 0.003), and higher C-reactive protein (P= 0.10). Weight loss was more common in adolescents (P= 0.006). Kidney (P= 0.004), eye (P= 0.005), and liver involvement (P= 0.03) were more common in Black patients. Regression analysis identified no single factor associated with positive treatment outcomes.ConclusionMultiorgan involvement, response to steroids, and chronic course are hallmarks of pediatric sarcoidosis. The phenotype significantly varies by age and race. Where conventional DMARDs were not efficacious, the addition of an anti-TNF agent was beneficial.

Objectives The objectives of this study were (i) to describe the clinical presentation, treatment and outcome of paediatric inflammatory multisystem syndrome temporally related to Sars-CoV-2 (PIMS-TS) in children; (ii) to propose a framework to guide multidisciplinary team (MDT) management; and (iii) to highlight the role of the paediatric rheumatologist in this context. Methods This study involved a retrospective case notes review of patients referred to a single specialist paediatric centre with suspected PIMS-TS, with a focus on clinical presentation, laboratory parameters, treatment, and outcome in the context of an MDT framework. Results Nineteen children of median age 9.1 years fulfilled the definition of PIMS-TS and were managed within an MDT framework: 5/19 were female; 14/19 were of Black, Asian or minority ethnicity; 9/19 also fulfilled diagnostic criteria for complete or incomplete Kawasaki disease (KD). Severe systemic inflammation, shock, and abdominal pain were ubiquitous. Treatment was stratified within an MDT framework and included CSs in all; i.v. immunoglobulin in all; anakinra in 4/19; infliximab in 1/19; and antiviral (aciclovir) in 4/19. Conclusions We observed significant diagnostic equipoise using a current definition of PIMS-TS, overlapping with KD. Outside of clinical trials, an MDT approach is vital. The role of the paediatric rheumatologist is to consider differential diagnoses of hyperinflammation in the young, to advise on empiric immunomodulatory therapy, to set realistic therapeutic targets, to gauge therapeutic success, to oversee timely step-down of immunomodulation, and to contribute to the longer-term MDT follow-up of any late inflammatory sequelae.

Background Dacryoadenitis is an inflammatory enlargement of the lacrimal gland and can be idiopathic or associated with infections, malignant or inflammatory diseases like Sjögren’s disease (SSj) or granulomatosis with polyangiitis (GPA). It remains the most common orbital inflammatory condition in children. This study purposes to describe a paediatric cohort of non-infectious dacryoadenitis. Methods Identification of children who underwent lacrimal gland biopsy at our centre between 2000 and 2018 was done by searching the database using two key-words: “lacrimal” and “dacryoadenitis”. Patients with infectious or malignant dacryoadenitis were excluded. Medical notes were reviewed to collect data. Results Twenty-six patients underwent lacrimal gland biopsy at our centre between 2000 and 2018 and had inflammatory dacryoadenitis. 17 patients (65.4%) had non-specific chronic inflammation (NSCI) and 9 patients (34.6%) had an inflammatory systemic condition (Table 1). P53 Table 1Patients’ characteristics.NSCIGPASarcoidosisSSjogrenIgG4Number of patients17 (65.4%)4 (15.4%)3 (11.5%)1 (3.9%)1 (3.9%)Female, n (%)6 (35.3%)4 (100%)3 (100%)1 (100%)1 (100%)Median age (Y) (IQ)10.5 (4.9- 14.4)9.72 (8.7- 13.0)13.2 (11.45- 15.7)11.911.2Lacrimal gland involvementUnilateral13 (74.5%)3 (75.0%)2 (66.7%)00Bilateral4 (23.5%)1 (25.0%)1 (33.3%)1 (100%)1 (100%)Orbital symptomsPtosis4 (23.5%)1 (25.0%)000Erythema3 (17.5%)1 (25.0%)1 (33.3%)00Pain2 (11.8%)1 (25.0%)000Extra-orbital involvementExocrine glands001 (33.3%)00ENT03 (75.0%)000Renal1 (14.3%)2 (50.0%)01 (100%)1 (100%)Pulmonary1 (14.3%)1 (25.0%)1 (33.3%)01 (100%)Myositis1 (14.3%)0000Arthralgia1 (14.3%)01 (33.3%)00Thyroiditis1 (14.3%)0000CNS0001 (100%)0Lymphadenopaties00001 (100%) 4/13 children tested had raised ACE (2 sarcoidosis and 2 NSCI). 7/17 had raised amylase (2 sarcoidosis,1 SSj, 4 NSCI). 3/16 had raised IgG (IgG4 disease, GPA and NSCI). ANA was positive in 4/19 patients (NSCI, GPA, Sarcoidose, SSj) and ANCA was positive in 4/19 patients (GPA). Thirteen patients received steroids (oral or IV) and elevan received DMARDS (MMF, methotrexate, azathioprine and hydroxychloroquine). Four patients received biologic (rituximab, adalimumab or infliximab). Six patients underwent orbitotomy. Patients still on follow-up had good response to treatment. One patient with NSCI presented with dacryoadenitis and later developed auto-immune thyroiditis and polymyositis, with positive ANA and anti-SRP antibodies. He was treated with steroids, methotrexate, MMF and IVIG. Conclusion Paediatric rheumatic inflammatory disorders have a diverse presentation and dacryoadenitis may be the initial manifestation. Biopsy is mandatory to exclude infection and malignancy. A full diagnostic workup is essential, especially if patients have positive ANA or ANCA. Conflicts of Interest The authors declare no conflicts of interest.

Background There is a challenging lack of evidence to inform best practice in the routine clinical care of juvenile idiopathic arthritis (JIA). Wide inter-centre variation in the definition and documentation of clinical data items is a major barrier to improvement. In response, we have developed a consensus agreed standardised core dataset called CAPTURE-JIA (n = 62 data items and a ‘data dictionary’ including agreed definitions of terms) designed to support routine collection of high-quality clinical data. The feasibility and acceptability of CAPTURE-JIA in clinical practice is not yet known and was the focus of this pilot study. Methods A purposeful sample of six paediatric rheumatology centres across England was invited to collect the CAPTURE-JIA dataset using paper collection forms (n = 20 patients/centre). The dataset was analysed for missing data. Six focus groups (n = 3-10) explored clinicians’ views on acceptability and feasibility. Results One hundred and twenty-one patients were recruited over three months. The completeness of the dataset was similar across centres, with minor variations. The majority of data items (eg demographics, dates, ILAR type and examination) were >80% completed. However, 14/62 data items received >40% missing data. (Table 1) Further descriptive analyses highlighted incorrect completion of paper forms. Three themes emerged from the focus groups: problematic data items (missing from >10% forms at > 1 centre), format of clinician data forms and the role of digital data collection. Suggested solutions included minor changes to data item definitions and formatting. There were no refinements to the data items. Development of a digital data collection system was identified by all as essential. Due to a lack of clear consensus, the original CAPTURE forms included a number of ways to record joint count data. This proved confusing and a unanimous decision was taken to collect joint count data on all 83 joints in a tabular format. P10 Table 1: CAPTURE JIA data items with >40% missing data Data item % forms with data item missing (if item required) Relevant co-morbidities? 60 Macrophage activation syndrome? 100 Has the ILAR subtype changed? 50 Morning stiffness lasting >15 minutes? 42 History of any form of uveitis? 52 Date started uveitis mediation? 50 Strength of uveitis medication? 83 Counselled prior to new DMARD / biologic? 56 Enrolled in BECS/BCRD if new DMARD / biologic? 48 Joint count (homunculus or table format) 48 Physician assessment of systemic disease activity (VAS) 75 ESR 74 CRP 92 Plasma viscosity 100 Conclusion Paper collection of the CAPTURE-JIA data items is feasible and acceptable in the routine clinical setting, but unlikely to be sustainable in the longer term if collected in duplicate with medical notes. A digital tool in the clinical domain, ideally interlocking with local systems, would offer many advantages, including more complete and time-efficient data collection. Conflicts of Interest The authors declare no conflicts of interest.

Background Paediatric sarcoidosis represents a spectrum of disease. Early onset sarcoidosis & Blau syndrome associated with NOD2 mutations are characterized by fever, rash, arthritis & organomegaly. Later onset sarcoidosis has wider organ involvement (lungs, kidneys, lachrymal & extra-ocular glands). Both presentations may lead to long term complications due to end-stage organ damage. Ocular sarcoidosis has a well described uveitis phenotype. We aim to describe a retrospective cohort of children with sarcoid-like uveitis & their systemic manifestations at time of study; compare cohort of patients fulfilling IWOS criteria for ocular sarcoidosis versus who did not; and describe their management in retrospective cohort. Methods We performed a retrospective case review of all children currently followed at GOSH with ocular sarcoidosis phenotype with uveitis (ophthalmologist definition based on IWOS, or diagnosis of idiopathic uveitis with raised ACE level at least once. We collected demographics & all extra-ocular involvement described in sarcoidosis. Results n = 52; 27/52 males. Median age at onset of uveitis 4.20 years (1.41-15.16). 49/52 bilateral uveitis. 27/52 (50%) 1:80) in 15/47 (32%). Systemic involvement (n = 52): arthritis 29%, liver 29%, lymphadenopathy 19%, renal 16%, lungs 15.3%, skin 17.3%, spleen 7.7%, glands 1.9%. Patients as per adult IWOS criteria: Definite 12/52, Presumed 6/52, Probable7/52 and Not fulfilling – 27/52. Systemic involvement in patients not fulfilling IWOS criteria (27/52) – renal 14.8%, arthritis 22.2%, hilar or peripheral lymphadenopathy 0 %, skin involvement 7.4%, lung 18.5%, splenomegaly 3.7%. Comparing IWOS fulfilling (25) with the ones who did not (27) – systemic involvement consistently less common in the ones NOT fulfilling but only reaches statistical significance difference for involvement. Lymphadenopathy and skin (p < 0.001 and p < 0.050 respectively). Suggesting that paediatric age group cannot be classified as per the adult IWOS ocular sarcoidosis criteria and needs early systemic screening. Medications used to treat uveitis and/or extra-ocular manifestations: methotrexate alone 25%, methotrexate + adalimumab 21.1%, mycophenolate mofetil 9.61%, only systemic steroids 3.8%. 9 patients- no systemic medications at any time during their disease. Conclusion Most sarcoid-like uveitis patients had at least one systemic involvement. 51.9% patients did not fulfil the IWOS ocular sarcoidosis criteria, still had systemic involvement. Hilar lymphadenopathy criteria cannot be applied to the paediatric population, peripheral more common. ACE not a sensitive biomarker to predict sarcoidosis. 17.3 % had mild phenotype & required no treatment. This study demonstrates the importance of close monitoring for systemic manifestations & highlights good clinical response to steroids, MTX, MMF and anti-TNF. Conflicts of Interest The authors declare no conflicts of interest.

Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NBS) are 2 overlapping syndromes caused by mutations in genes of the BRG1/BRM-associated factor chromatin-remodeling complex, presenting with multiple malformations and intellectual disability. Musculoskeletal changes such as noninflammatory prominence of interphalangeal joints in hands, feet, and, to a lesser extent, knee joints are common in NBS (up to 85%) and also reported in CSS. We present the case of a 7-year-old boy with polyarthritis of several years’ duration (without uveitis), developmental delay, microcephaly, and dysmorphic features reminiscent of NBS. Sanger sequencing of the SMARCA2 gene revealed no mutations. Laboratory test results were normal. With synovial biopsy, we confirmed a chronic inflammatory synovitis. Brain MRI revealed dysgenesis of the corpus callosum. Treatment with methotrexate and, subsequently, etanercept led to significant clinical improvement. Whole-exome sequencing revealed a de novo heterozygous nonsense mutation in the ARID1B gene, resulting in a premature stop codon (c.C5404T; p.R1802×), a genotype consistent with CSS. The absence of significantly raised inflammatory markers and a clinical diagnosis of a genetic syndrome associated with noninflammatory joint changes may have contributed to this patient’s polyarthritis being missed for several years. We propose that some patients with CSS may have inflammatory arthritis (with or without coexisting skeletal dysplasia), which may be helped by treatment as described herein. Early recognition and treatment of inflammatory arthritis in CSS would have a significant impact on reducing disease burden and improving quality of life for patients with this rare genetic syndrome.

Background Mono-allelic mutation in tumor necrosis factor alpha induced protein 3 (TNFAIP3) has been found to cause haploinsufficiency of A20 protein, the cause of an early-onset auto inflammatory disease resembling Behcets’s disease (BD). Single nucleotide polymorphism in TNFAIP3 may also contribute to susceptibility to systemic lupus erythematosus (SLE). Several mutations in TNFA1P3 have been shown to be disease-causing, including a single case with heterozygous mutation in the TNFAIP3 gene for c.811C>T; p.(arg271*) with a BD-like phenotype. Objectives To report the case of a child with heterozygous mutation TNFAIP3 (c.811C>T; p.(arg271*) with an unusual SLE/SS (Sjoegren syndrome) phenotype, thus expanding the phenotype associated with this mutation; and describe the disease course and treatment Methods Clinical details were retrospectively collated using routine clinical records. The molecular cause of the phenotype was investigated using a targeted gene next generation sequencing (NGS) panel (the vasculitis and inflammation panel, VIP). Confirmation of findings detected by NGS were confirmed using conventional Sanger sequencing in the index case and subsequently in the parents. Results A 4yr old Caucasian female presented with a 2-year history of photosensitive malar rash, mouth ulcers, hair loss, arthralgia, livedo reticularis, cervical lymphadenopathy and hepatosplenomegaly. Laboratory tests revealed anemia, raised inflammatory markers and hypocomplementemia; RF, ANA and anti Ro positivity, raised C1q antibodies and low C1Q level. 7 out of 11 classification criteria for SLE were met and treatment with hydroxychloroquine was commenced. Subsequently she developed blepharitis, acute anterior uveitis, chilblains and discoid skin lesions. Azathioprine and oral steroids were added. Due to young age at disease onset, NGS screening was performed and revealed heterozygous mutation in TNFAIP3 c.811C>T; p.(Arg271*). Screening of both parents revealed the same mutation in the mother, who is asymptomatic. The child further developed Raynaud’s and underwent renal biopsy for intermittent proteinuria which revealed ISN/RPS Class III and V lupus nephritis. Azathioprine was switched to mycophenolate mofetil. One year later her skin symptoms continue to improve, uveitis is in remission and her renal function is normal. Prednisolone was tapered off. Conclusion We further expand the phenotype associated with mutation in the TNFAIP3; the c.811C>T; p.(arg271*) variant previously described as the cause of a BD-like-phenotype, in our case caused an auto immune disease with severe SLE/SS phenotype. This variant also demonstrated variable penetrance in our pedigree, since the mother harbours the same variant but remains asymptomatic. Thus, the genetic cause of monogenic lupus continues to expand, and the distinction between autoinflammatory and autoimmune disease is less clear-cut than first thought. References [1] Aeschlimann, F. A., & Laxer, R. M. (2018). Haploinsufficiency of A20 and other paediatric inflammatory disorders with mucosal involvement. Curr Opin Rheumatol, 30(5), 506-513. [2] Liu, X., Qin, H., Wu, J., & Xu, J. (2018). Association of TNFAIP3 and TNIP1 polymorphisms with systemic lupus erythematosus risk: A meta-analysis. Gene, 668, 155-165. [3] Zhou, Q., Wang, H., Schwartz, D. M., Stoffels, M., Park, Y. H., Zhang, Y., . . . Aksentijevich, I. (2016). Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet, 48(1), 67-73. Disclosure of Interests Kerstin Nott: None declared, Yvonne Glackin: None declared, Stephen D Marks Grant/research support from: chief investigator and principal investigator for pharma sponsored randomised controlled trials in children from Astellas and Novartis but receive no money personally as the income goes directly to our institutions., Paul Brogan Grant/research support from: SOBI, Novartis, Roche, Novimmune, Chemocentryx, Consultant for: Roche, SOBI, Speakers bureau: SOBI, Roche, Novartis, UCB, Sandrine Compeyrot-Lacassagne Grant/research support from: Abbvie

Background Paediatric sarcoidosis may represent a spectrum of disease. Early onset sarcoidosis & its genetically defined counterpart Blau syndrome associated with NOD2 mutations are characterized by fever, rash, arthritis and organomegaly. Later onset sarcoidosis has wider organ involvement including lungs, kidneys, lachrymal and extra-ocular glands. Both presentations may lead to long term complications due to end-stage organ damage. Although similar disease manifestations can be seen in adults and children, some entities are essentially pediatric at onset, namely Blau syndrome and most forms of immunodeficiency associated granulomatous diseases. Ocular sarcoidosis has a well described uveitis phenotype (1). We created a retrospective cohort of patients currently followed at GOSH with likely ocular manifestation of sarcoidosis (1) Objectives To describe a retrospective cohort of children with sarcoid-like uveitis, To describe their extra-ocular manifestations at the time of the study,To describe their management Methods: retrospective case review of children currently followed at GOSH with a phenotype of ocular sarcoidosis with uveitis (ophthalmologist defn (5, 6)), or a diagnosis of idiopathic uveitis (anterior, posterior, intermediate or panuveitis) with raised ACE level at least once. We collected demographics and all extra-ocular involvement described in sarcoidosis Results 52 patients. 27/52 males. Median age onset of uveitis 4.20 yrs (1.41-15.16). 30/52had onset Ethnicity: black 13, asian 10, caucasian 13, unknown 16/52. 49/52 patients had bilateral uveitis. Uveitis anterior 17/52, intermediate 5/52, posterior 2/52, panuveitis 25/52, unknown 1/52. ANA+15/47(32%). Extra-ocular (n=52): Lymphadenopathy: 15 (29%) clinically Liver: 16 (31%) - transaminitis 9, ultrasound(USS) abnormality (hepatomegaly, calcification, increased echogenicity) 5 & both abnormal USS & blood 2 Arthritis: 15 (29%) large joints of lower limbs & joints hands. Tenosynovitis 4 (7.7%) Renal: 15 (29%) (USS or Blood/urine tests – raised serum creatinine, raised urinary ca creat ratio, raised urinary NAG/RBP) — 4/15 on USS and 9/15 in blood/urine tests, 2/15 on both USS and blood/urine tests. Lungs: 7 (13.5%): 6 abnormal lung function test, 1abnormal CXR, lung function& CT chest - severe interstitial lung disease & presented- progressive shortness of breath. Skin: 10(19.2%), eczema-like/non-specific skin Parotid/glandular: 1 (1.9%) on USS Splenomegaly: 4 (7.7%) on USS Sensorineural hearing loss: 2 (3.8%) Medications to treat uveitis and/or extra-ocular manifestations were: Methotrexate 13 (25%), Methotrexate + Adalimumab 11 (21.2%), MMF 6 (11.5%), topical steroids 8 (15.4%), systemic steroids 2 (3.8%). 10 patients no medication Conclusion Most of the sarcoid-like uveitis patients had at least one extra-ocular involvement. ACE does not appear to be a sensitive biomarker. Some patients (19.2%) have a mild phenotype and require no treatment. Our data demonstrate the importance of close monitoring for extra-ocular manifestations and highlight good clinical response to steroids, MTX, MMF and anti-TNF. Reference [1] Acharya NR et al International Ocular Sarcoidosis Working Group. Distinguishing Features of Ocular Sarcoidosis in an International Cohort of Uveitis Patients. Ophthalmology. 2018 Jan;125(1):119-126. Disclosure of Interests Abhay Shivpuri: None declared, Emily Kalms: None declared, Ameenat Lola Solebo: None declared, Harry Petrushkin: None declared, Dhanes Thomas: None declared, Elizabeth Graham: None declared, Clive Edelsten: None declared, Sandrine Compeyrot-Lacassagne Grant/research support from: Abbvie

Background Childhood uveitis is a group of heterogenous, potentially blinding inflammatory disorders. Management is complex. There is growing recognition of the importance of actively involving affected children and their families in their own care. Co-designed interventions, developed through active involvement of staff and patients, can provide effective solutions to problems identified by those affected. Objectives To use findings from a patient and family discussion group to inform the co-designed development of health care processes and interventions. Methods Five children/young people with uveitis (age ranges 8 to 17), seven parent/carers of children with uveitis and four health care professionals attended a 90 minute discussion group. Main discussion topic was the identification of areas in need of interventions or support structures. Sub-topics were determined a priori using previous PPI and existent research (REFS). They comprised: Direct health care; Impact on families; School, education and peers. Responses were collated. Consent was taken for use of direct quotes from participants. Results We outline the areas identified by children and families: Direct health care Four interconnected areas were identified: (1) Transitioning to adult services, (2) peer support (health care services being a valuable site for identifying peers), (3) communication between care structures, and (4) education for families. With regards to family education, there was identification of the need for specific services or interventions around the communication of (4a) diagnosis, (4b) treatment, (4c) likely long term outcomes/prognosis, (4d) and the child’s progress. There was also discussion on (4e) the formats used to communicate with families. Impact on families Participants discussed support around (1) family relationships, (2) the impact of systemic medication. They also discussed (3) a need for recognition of the changing nature of their lived experience as affected families over the disease course and the need for on-going psychologic support especially at presentation to help with acceptance. School, education and peers Participants discussed the need for support around: (1) the impact of treatment on school life, (2) communication with school professionals and peers, (3) impact of visual impairments, (4) managing the visibility/invisibility paradox (ie being made to feel different but also having a disorder which was not externally apparent), and (5) managing adolescence. Conclusion Through the above approach, we have identified a range of issues affecting our patients and their families. Our findings are similar to those of other groups (1, 2) These lived experiences will be used to inform the co-design of supportive services (patient leaflets, videos, website, psychology intervention) and research on the effectiveness of these interventions in improving the management of affected children and their families. References [1] Parker DM, Angeles-Han ST, Stanton AL, Holland GN. Chronic Anterior Uveitis in Children: Psychosocial Challenges for Patients and Their Families. Am J Ophthalmol. 2018 Jul; 191:xvi-xxiv [2] Silva LMP, Arantes TE, Casaroli-Marano R, Vaz T, Belfort R Jr, Muccioli C. Quality of Life and Psychological Aspects in Patients with Visual Impairment Secondary to Uveitis: A Clinical Study in a Tertiary Care Hospital in Brazil. Ocul Immunol Inflamm. 2017 Oct 11:1-9. Disclosure of Interests Sandrine Compeyrot-Lacassagne Grant/research support from: Abbvie, Christine Twoney: None declared, Harry Petrushkin: None declared, Dhanes Thomas: None declared, Emily Robinson: None declared, Lucia Kossarova: None declared, Ameenat Lola Solebo: None declared

Background: Dacryoadenitis is an inflammatory enlargement of the lacrimal gland and the most common orbital inflammatory condition in the paediatric population, although only 6 to 17% of orbital inflammatory disorders occur in children (1-4). Dacryoadenitis may be idiopathic or associated with infections or inflammatory diseases. Systematic inflammatory disorders are more typically associated with chronic than acute dacryoadenitis (3). We describe the largest paediatric cohort of biopsy proven non-infectious dacryoadenitis (4,5). Objectives: To describe lacrimal gland biopsy results To report associated clinical, laboratory features and treatment Methods: We identified 72 children who had lacrimal gland biopsy at GOSH between 25/09/2000 and 12/04/2018 using two key-words: “lacrimal” and “dacryoadenitis”. We excluded patients with infectious dacryoadenitis, benign tumors or malignancy. We retrospectively reviewed the medical notes, laboratory and histopathology results. Results: Twenty six patients had non-infectious dacryoadenitis with or without soft tissue involvement. All cases manifested as upper lid swelling. 19 (73.1%) patients had unilateral involvement. 12 (46.2%) patients were male. Mean age at time of biopsy was 10.5 years and median 13 years (range 1 – 17.7). Four patients had GPA (granulomatous polyangiitis), 4 patients sarcoidosis, 1 patient IgG4-related disease, 1 patient Sjogren with secondary anti-phospholipid syndrome and 16 patients non-specific chronic inflammation (NSCI). 2/4 patients with sarcoidosis had extra-ocular involvement. One patient with sarcoidosis had NOD2 mutation without Blau phenotype. One patient with GPA had extra-ocular involvement. 4/13 children tested had raised ACE including 2 sarcoidosis and 2 NSCI. 7/17 had raised amylase (2 sarcoidosis, 1 Sjogren, 4 NSCI). 7/20 had raised ESR (1 Sjogren, 5 NSCI and 1GPA with renal involvement). 3/16 had raised IgG (IgG4 disease, GPA with renal involvement and NSCI). 13 (50%) patients received systemic steroids. 11 (42.3%) patients received DMARDS (MMF, Methotrexate, Azathioprine and Hydroxychloroquine). 4 (15.4%) patients received a biologic: 3/4 rituximab (2 GPA and one IgG4-related disease) and one patient with NSCI received anti-TNF. 6 (23.1%) patients underwent orbitotomy. Patients still on follow-up had good response to treatment and did not experience any local complication. One patient with NSCI developed auto-immune thyroiditis and polymyositis. Conclusion: Most of the patients in our retrospective cohort study had NSCI and may be idiopathic. Few patients had a specific diagnosis on biopsy allowing targeted treatment. Patients with non-infectious dacryoadenitis may benefit from tissue biopsy to exclude infection and malignancy and streamline management. On-going monitoring is important for patients with NSCI to identify underlying inflammatory diseases at an early stage. References [1] Belanger C, et al. Inflammatory Disorders of the Orbit in Childhood: A Case Series. Am J Ophthalmol. 2010Oct;150(4):460-3 [2] Spindle J, Tang SX, Davies B, Wladis EJ, Piozzi E, Pellegrini M, Lally SE, Shields C, Shinder R. Pediatric Idiopathic Orbital Inflammation: Clinical Features of 30 Cases. Ophthalmic Plast Reconstr Surg. 2016 Jul-Aug;32(4):270-4 [3] Andrew NH, Kearney D, Sladden N, McKelvie P, Wu A, Sun MT, McNab A, Selva D. Idiopathic Dacryoadenitis: Clinical Features, Histopathology, and Treatment Outcomes. Am J Ophthalmol. 2016Mar;163:148-153 [4] Luemsamran P, Rootman J, White VA, Nassiri N, Heran MKS. The role of biopsy in lacrimal gland inflammation: A clinicopathologic study. Orbit. 2017Dec;36(6):411-418 [5] Boulter EL, Eleftheriou D, Sebire NJ, Edelsten C, Brogan PA. Inflammatory lesions of the orbit: a single paediatric rheumatology centre experience. Rheumatology2012. 51(6):1070–1075 Disclosure of Interests: Joana Silva-Dinis: None declared, Ameenat Lola Solebo: None declared, Yassir Abou-Rayyah: None declared, Sandrine Compeyrot-Lacassagne Grant/research support from: Abbvie

Purpose To investigate the cost effectiveness of adalimumab in combination with methotrexate, compared with methotrexate alone, for the management of uveitis associated with juvenile idiopathic arthritis (JIA). Design A cost-utility analysis based on a clinical trial and decision analytic model. Participants Children and adolescents 2 to 18 years of age with persistently active uveitis associated with JIA, despite optimized methotrexate treatment for at least 12 weeks. Methods The SYCAMORE (Randomised controlled trial of the clinical effectiveness, SafetY and Cost effectiveness of Adalimumab in combination with MethOtRExate for the treatment of juvenile idiopathic arthritis associated uveitis) trial (identifier, ISRCTN10065623) of methotrexate (up to 25 mg weekly) with or without fortnightly administered adalimumab (20 or 40 mg, according to body weight) provided data on resource use (based on patient self-report and electronic records) and health utilities (from the Health Utilities Index questionnaire). Surgical event rates and long-term outcomes were based on data from a 10-year longitudinal cohort. A Markov model was used to extrapolate the effects of treatment based on visual impairment. Main Outcome Measures Medical costs to the National Health Service in the United Kingdom, utility of defined health states, quality-adjusted life-years (QALYs), and incremental cost per QALY. Results Adalimumab in combination with methotrexate resulted in additional costs of £39 316, with a 0.30 QALY gain compared with methotrexate alone, resulting in an incremental cost-effectiveness ratio of £129 025 per QALY gained. The probability of cost effectiveness at a threshold of £30 000 per QALY was less than 1%. Based on a threshold analysis, a price reduction of 84% would be necessary for adalimumab to be cost effective. Conclusions Adalimumab is clinically effective in uveitis associated with JIA; however, its cost effectiveness is not demonstrated compared with methotrexate alone in the United Kingdom setting.

Objective.Growth retardation is a frequent complication of severe juvenile idiopathic arthritis (JIA). Biologic treatments may improve growth velocity by controlling systemic inflammation and reducing corticosteroids. Our goals were to compare growth velocity before and after the onset of biologic therapy and to determine whether the JIA subtype, the use of steroids, the requirement of one or several biologic agents, or the disease activity influenced growth velocity.Methods.We retrospectively analyzed the growth of children with JIA who never received growth hormone treatment, who started biologic treatment before puberty, and who were followed for at least 6 months afterward.Results.We included 100 children (33 boys). Median patient age was 7.1 years (range: 1.6–15.7) at the onset of biologic treatment and 11.0 years (range: 2.3–19.5) at the latest followup. Forty-six patients had received corticosteroid and 34 had received more than 1 biologic agent. Patient median height expressed as SD score (SDS) was 0.31 (range: −2.47 to 5.46) at disease onset, −0.24 (−3.63 to 2.90) at biologic therapy onset (p < 0.0001), and −0.15 (−4.95 to 3.52) at the latest followup (p = 0.171 compared to biologic treatment onset). Patients who required several biologics and systemic patients had a significantly lower growth velocity after the onset of biologic treatment. At the latest followup, 18% of our study group had low growth velocities and 19% were below −2SD or shorter than genetically programmed.Conclusion.In a subset of patients, particularly systemic JIA patients and patients who required more than 1 biologic, biologic therapy may be insufficient to restore normal growth velocity.

To the Editor: Juvenile idiopathic inflammatory myopathy (JIIM) refers to a group of rare chronic autoimmune conditions. Juvenile dermatomyositis (JDM) is the most common JIIM. The hallmarks of JDM are characteristic cutaneous features and proximal muscle weakness; however, adermatitic forms have been described. Polymyositis presents with both proximal and distal muscle weakness, muscle atrophy, and similar degrees of dysphagia, arthritis, and contractures1. Although magnetic resonance imaging (MRI) is widely used, muscle biopsy remains a critical tool in the diagnosis of JIIM, especially in atypical cases1. Recently, LMNA -associated congenital muscular dystrophy (LMNA-CMD) has been reported as a novel and severe form of laminopathy with secondary inflammatory changes mimicking inflammatory myopathies2,3. Mutations in the LMNA gene encoding lamin A/C are responsible for multiple disease phenotypes4. Some of them may present early in life as a congenital muscular dystrophy2,3. ### Patient We report the case of a 26-month-old girl, first child of non-consanguineous parents, who was referred to our department based on a history of progressive muscle weakness with raised creatine kinase (CK) and a muscle biopsy showing marked inflammation. There was no family history of neuromuscular or autoimmune diseases. She was born by normal uncomplicated delivery; no reduced fetal movements were described by the mother during pregnancy. By 1 year of age, she was … Address correspondence to Dr. E. Moraitis, Rheumatology Department, Great Ormond Street Hospital for Children, Great Ormond Street, London, WC1N 3JH, UK. E-mail: elena.moraitis.13{at}ucl.ac.uk

Objectives. To investigate the functional status of difficult-to-treat JIA patients, including patients receiving biotherapies, and to correlate functional status to disease activity. Methods. All JIA patients consecutively evaluated in a paediatric rheumatology referral centre (November 2008 to March 2009) were enrolled in an observational cross-sectional study. The Childhood HAQ (CHAQ), physician’s assessment of overall disease activity, parent’s assessment of well-being and pain, and active and limited joint numbers were measured. Results. We enrolled 95 patients [27% systemic, 29% polyarticular, 22% enthesitis-related arthritis (ERA) and 23% oligoarticular JIA]. Median disease duration was 3.5 years. Treatment included NSAIDs (56%), MTX (23%), CSs (21%) and biologics (45%). Of all patients, 31 and 56%, respectively, had inactive and minimally active disease. The median CHAQ score was 0.375 (range 03). Most patients had no or mild functional disability (61%), impaired well-being (63%) or pain (55%); 10% reported severely impaired function and well-being, 19% severe pain. ERA patients reported worse well-being and pain. CHAQ scores correlated with disease activity. Long-lasting disease and biologic treatment were associated with better well-being and pain scores. Conclusion. Despite the high proportion of severe JIA patients in this cohort, CHAQ values are within the lower range of recent reports, probably related to new therapeutic approaches. Impaired function and well-being remain a challenge for at least 10% of the patients. Impaired well-being and pain in ERA patients require further study. The strong correlation between functional status and well-being underlines the importance of improving function to optimize quality of life.

Objective Studies of adults with systemic lupus erythematosus (SLE) have frequently demonstrated the presence of decreased bone mineral density (BMD). However, there have been few investigations in pediatric patients to date. This study was undertaken to determine the prevalence of low BMD in patients with juvenile SLE and to identify associated risk factors. Methods We studied 64 consecutive patients with juvenile SLE in whom routine dual x-ray absorptiometry (DXA) scanning was performed. Lumbar spine osteopenia was defined as a BMD Z score of

A considerable proportion of children with polyarticular juvenile idiopathic arthritis (polyJIA) experience active disease into adulthood.1 However, there is no validated disease activity measure for adults with polyJIA, and they are often assessed using the disease activity score 28 (DAS28). DAS28 is validated in adults with rheumatoid arthritis (RA), and determines qualification for biological drugs in the UK and other countries.2 ,3 In contrast to the juvenile arthritis disease activity score (JADAS),4 DAS28 does not fully evaluate the pattern of joint involvement often observed in polyJIA. In this study, we compared DAS28 with JADAS-10 in adolescents and adults with polyJIA. Tender and swollen joint counts out of 28, active joint count of all joints up to a maximum of 10, patient/parent and physician global assessment visual analogue scales were collected from clinics in patients aged ≥10 years with polyJIA (International League of Associations for Rheumatology classification criteria for rheumatoid factor-negative (RhF-ve) or rheumatoid factor-positive (RhF+ve) polyJIA). Erythrocyte sedimentation rate (ESR) values were taken within 30 days before or after assessment. When unavailable, values were taken within 3 months before or after, provided the patient remained stable between the ESR test and assessment. When unavailable within these time periods, patients were excluded from …

The autoinflammatory diseases (AID) include monogenic and polygenic disorders characterized by primary dysfunction of the innate immune system.

International audience; BACKGROUND: Anakinra pharmacokinetics and pharmacodynamics were investigated in children and adolescents treated for systemic-onset juvenile idiopathic arthritis (SJIA) and autoinflammatory syndromes. METHODS: Anakinra was given subcutaneously at doses between 2 and 10 mg/kg (maximum 100 mg) per day. Anakinra concentrations were recorded in patients, as well as C-reactive protein (CRP) levels, on different occasions. The data were fitted to a pharmacokinetic-pharmacodynamic model via a population approach using Monolix. RESULTS: A total of 87 children and adolescents, 8 months to 21 years old, were available for pharmacokinetic evaluation. A one compartment model with linear absorption and elimination described the pharmacokinetics. Taking into account bodyweight to explain variations in apparent clearance (CL/F) and distribution volume (V/F) significantly reduced the associated between-subject and between-occasion variabilities. The final estimates were 6.24 L/h/70 kg and 65.2 L/70 kg for CL/F and V/F respectively. A mixture pharmacodynamic model described the CRP level change during anakinra treatment for the SJIA patients with 2 subpopulations, patients with high baseline and large CRP decrease and patients with low baseline and small CRP decrease followed by a re-increase in CRP levels. There was no significant effect of the combined anti-inflammatory treatment. The proportion of patients for which the development of a resistance to treatment was significant was 62% and the corresponding time was approximately 60 days CONCLUSIONS: Based on effects in SJIA, a prospective dosage adjustment was proposed based on a 0.4 mg/L Css target in order to obtain a CRP decrease to 10 mg/L or below.

OBJECTIVE To assess the clinical characteristics of patients living in France and carrying a single MEFV mutation. METHOD A retrospective chart review of patients referred to us for recurrent fevers. Genetic testing: systematic screening of exons 2 and 10 was performed in the MEFV gene. A subset of patients was also investigated for other auto-inflammatory genes. RESULTS We analysed 94 patients (sex ratio:1). Forty-two percent of them were Jews and 17% were Arabs. The median age of onset was 2 years (3 months-47 years). Fever was >39 degrees C in 80% of them, while the duration and frequency of an attack varied ( 3 days: 36%; >2 months: 15%; 1-2 months: 48%; and

Noninfectious inflammatory lesions of the mandible occur in chronic recurrent multifocal osteomyelitis (CRMO). Diffuse sclerosing osteomyelitis of the mandible (DSOM) is a condition thought to be a localized form of CRMO. Recently, bisphosphonate therapy, and particularly intravenous pamidronate, has been proposed as a treatment for patients with both CRMO and DSOM who do not improve with nonsteroidal antiinflammatory drug treatment. We report our experience using pamidronate in 2 children with chronic noninfectious osteomyelitis affecting the mandible. We describe the clinical and radiographic features and the treatment, side effects, and clinical and radiographic responses. Our experience suggests that pamidronate is an effective second-line therapy.

Background JIA-associated uveitis is an insidious and often asymptomatic complication of JIA. Up to 30% of patients with JIA will develop uveitis depending of their disease9s subgroup, the extended oligoarticular JIA being the most often affected group. There is also evidence of an association with positive ANA. More than 50% of patients with JIA-associated uveitis will develop complications including cataract and glaucoma. Although the risk of blindness is low, the risk of functional impairment is much higher. Increasing uveitis activity was associated with increased risk of vision loss. Use of immunosuppressive drugs was associated with reduced risk of vision loss. Control of inflammation and use of immunosuppression may be critical aspects in improving outcome although little evidence is yet available. Objectives To identify the proportion of patients with JIA-associated uveitis who discontinued Methotrexate (MTX) due to remission To identify the proportion of patients with JIA-associated uveitis who require an anti-TNF biologic agent for the management of uveitis Methods We conducted a retrospective review of the clinical notes of patients diagnosed with JIA-associated uveitis between 1993 and 2009. We excluded the patients who did not require systemic treatment and those with incomplete record. We identified a total of 81 patients. Results MTX was stopped due to remission in 18 patients (22.2%) but 3 patients were started on an anti-TNF. Therefore, only 15 patients (18.5%) could stop MTX due to remission without using systemic medication. MTX was stopped in 13 patients (16.0%) due to side effect or non-compliance. In that group, six patients were switched to other immunosuppressive drugs including anti-TNF in four patients. MTX was continued in the remaining 50 patients (61.7%). Biologics and Cyclosporin A were added as in 11 and 4 patients respectively for further disease control. For those on additional Cyclosporin A, 3/4 patients were switched to an anti-TNF later. In the group of patients remaining on MTX, 14/50 patients (28%) required the addition of an anti-TNF for the control of their uveitis. Some of the patients in the MTX group have been on this medication for over 10 years. In summary, 21/81 patients (25.9%) have been on an anti-TNF agent and 14/21 patients have been receiving a biologic along with MTX. At the last follow up, 57/81 patients (70.7%) required long term systemic immunosuppression mostly MTX (87.7%). 21 (36.8%) out of the 57 patients were started on anti-TNF either with MTX or alone. Conclusions Over 2/3 of the patients have to remain on long-term systemic immunosuppression (mostly MTX) for the management of their uveitis. About 1/3 of them require long-term anti-TNF therapy either alone or along with MTX. Although this has led to a better visual functional outcome, it is associated with potential side-effects which need monitoring and an increased cost of management. Disclosure of Interest None declared

Background CRMO is a rare inflammatory bone disorder presenting with relapsing and remitting episodes of bone pain. It affects predominantly females between the age of 9 and 14. Insidious onset of bone pain in one or multiple sites may be associated with localised swelling and warmth. Objectives To assess the value of bone scan (BS) and MRI in the detection of bone inflammation. To correlate the imaging findings with inflammatory markers and clinical symptoms/location of pain. Methods We performed a retrospective review of the clinical notes of children with a confirmed diagnosis of CRMO who had both bone scan and MRI between September 2009 to September 2014 and within 9 weeks of each other. We recorded for each patient: inflammatory markers at time of scans (ESR, CRP and WCC), clinical symptoms/location of pain. Patients were excluded if both scans were done more than 9 weeks apart or if there was any change to treatment in-between scans. We recorded for both bone scan and MRI the number and the location of lesions. Results We identified nine patients (7 females, 2 males) who had CRMO and both bone scan and MRI less than 9 weeks apart. Despite a retrospective design and a small data set, we could observe that inflammatory markers appear non-specific, pain is often associated with a bone lesion on imaging, there are many additional asymptomatic lesions, pain can be referred, MRI and BS are equivalent in 44% of cases, there is no false negatives with BS, MRI is consistently detecting more lesions, BS may be better at detecting lesions in ribs and MRI detects more lesions in the spine. Conclusions The nature of these additional lesions seen on MRI is questionable as it is known that bone marrow oedema can be seen in normal children. Specificity and clinical importance of the MRI-positive but bone scan-negative lesions are still contentious issues. High quality BS is essential, with spot view and the right level of reporter experience. BS remains more easily accessible than MRI and contributes to the diagnosis of CRMO. Further studies are needed to establish sensitivity and specificity of both imaging. Disclosure of Interest None declared

Background Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children. Children with JIA are at risk of inflammation of the uvea in the eye (uveitis). Overall, 20% to 25% of paediatric uveitis is associated with JIA. Major risk factors for development of uveitis in JIA are oligoarticular pattern of arthritis, an age at onset of arthritis of less than seven years of age, and antinuclear antibody positivity. In the initial stages of mild to moderate inflammation the uveitis is asymptomatic. This has led to current practice of screening all children with JIA for uveitis. Approximately 12% to 38% of patients with JIA develop uveitis in seven years following onset of arthritis. In 30% to 50% of children with JIA-associated uveitis structural complications are present at diagnosis. Furthermore about 50% to 75% of those with severe uveitis will eventually develop visual impairment secondary to ocular complications such as cataract and glaucoma. Defining the severity of inflammation and structural complications in uveitis patients is now possible following Standardised Uveitis Nomenclature (SUN) guidelines, and modified to incorporate the consensus of end point and outcome criteria into the design of randomised trials. Despite current screening and therapeutic options (pre-biologics) 10% to 15% of children with JIA-associated uveitis may develop bilateral visual impairment and certified legally blind. To date, there remains no controlled trial evidence of benefits of biologic therapy. Methods/design This study will randomise 154 patients aged 2 to 18 years with active JIA-associated uveitis (despite methotrexate (MTX) treatment for at least 12 weeks). All participants will be treated for 18 months, with follow up of 3 years from randomisation (continuing on MTX throughout). All participants will receive a stable dose of MTX and in addition either adalimumab (20 mg/0.8 ml for patients

Background Scleroderma is a connective tissue disorder that is associated with changes in the skin and sometimes in internal organs. Digital ulcers in these patients can be difficult to treat and are associated with significant morbidity. Published literature shows that bosentan, an oral endothelin receptor antagonist has been useful in the treatment of digital ulcers in adults with scleroderma. However there has been no such literature published on paediatric patients. Objectives To evaluate the clinical response of three patients with digital ulcers treated with bosentan. Methods We present our experience of treating three children with systemic sclerosis and digital ulcers with bosentan. Case1: 12 year old female patient with diagnosis of systemic sclerosis/juvenile dermatomyositis overlap presented with Raynaud’s phenomenon, heliotrope rash, digital ulcers, tightening around mouth, exertional dyspnoea, rash over knuckles and nail fold capillary dilatation. Her bloods revealed she was ANA positive 1:2560 speckled pattern and ENA and RF positive. She had abnormal capillaries, oesophageal dysmotility and interstitial lung disease. Case 2: 10 year old female patient presented with linear skin lesions on thigh, exertional dyspnoea, dysphagia, digital ulcers and Raynaud’s phenomena. Her bloods revealed she was ANA positive 1:2560 homogenous pattern, ENA and AntiSCL antibody positive. She had an abnormal capillaroscopy, oesophageal dysmotility and interstitial lung disease. Case 3: 8 year old female patient had diffuse cutaneous skin disease, severe digital ulcers, hypopigmeted rash on knuckles, abnormal nail fold capillary dilatation and hypertension on presentation. Her bloods revealed she was ANA positive 1:2560 and anti U3RNP antibody positive. She had abnormal capillaries and oesophageal dysmotility but no interstitial lung disease. 2 patients were treated with bosentan at dose of 125 mg twice daily and one patient received between 125 mg to 250 mg twice daily. All the three patients were treated with nifedipine and glyceryl trinitrate patches for Raynaud’s phenomenon. They received systemic treatment including steroids and methotrexate, two of these patients received cyclophosphamide, one patient received mycophenolate mofetil and one patient received infliximab and subsequently adalimumab in addition. The third patient described had severe digital ulcers requiring iloprost/epoprostinol initially. Results Case 1 (scleroderma/juvenile dermatomyositis overlap) showed good response to bosentan. She had fewer new ulcers and her digital ulcers completely resolved. In this case bosentan was stopped after 4 years. Case 2 and 3 (systemic sclerosis) have been on bosentan for 18 months and 6 months respectively. Ulcers present at the time of diagnosis improved and there were fewer new ulcers in these patients. None of the three patients had side effects related to bosentan. Conclusions In our experience we have found bosentan to be safe and useful in the treatment of digital ulcers in these three children with scleroderma. Disclosure of Interest None Declared

Background The autoinflammatory syndromes (AISs) include monogenic and polygenic disorders characterized by primary dysfunction of the innate immune system. Objectives To describe the clinical spectrum, genetic background and therapy in a cohort of AIS patients followed in a reference Pediatric Rheumatology center. Methods Medical records of AIS patients followed until November 2010 and entered in the Eurofever Registry were studied. Results Fifty six patients were included: 17 CAPS, 4 TRAPS, 5 HIDS, 18 FMF, 6 CRMO, 2 SAPHO and 4 Behcet’s Disease (BD). The median follow-up was 2 years (0-14 years). The male/female ratio was 20/36. The median age was 2.5 years at disease onset and 4 years at diagnosis. Family history was positive in 34% of patients. Clinical manifestations included fever (79%), musculoskeletal (77%), gastrointestinal (63%), mucocutaneous (61%), neurological (41%), ocular (34%), cardiorespiratory (13%), and genitourinary (2%) findings, lymphadenopathy with/or hepatosplenomegaly (16%) and growth impairment (25%). The main organ system manifestations were arthralgia (70%), abdominal pain (50%), urticarial rash (34%), headache (34%), conjunctivitis (16%), generalized lymph node enlargement (13%), and chest pain (9%). Complications/sequelae developed in 45% of patients and involved the musculoskeletal (25%), neurological (21%), gastrointestinal (11%) and ocular (7%) systems. Six patients presented with severe/unusual manifestations: neonatal peritonitis (1 CAPS), pancreatitis (1 TRAPS), acute glomerulonephritis (1 FMF), complicated Henoch-Schonlein purpura (1 FMF), peritoneal adhesions with intestinal occlusion (1 FMF), periorbital pain (1 CRMO) and cerebral thrombosis (1 BD). AISs were associated with other diseases in 2 patients (FMF/Henoch-Schonlein purpura and CRMO/enthesitis-related arthritis). One mutant allele was found in 16/17 CAPS, 4/4 TRAPS and 4/18 FMF patients. Two mutant allelles were present in 5/5 HIDS and 11/18 FMF patients.The most used therapeutic agents were biologics (54%) (anakinra, canakinumab, etanercept, adalimumab), NSAIDs (48%), colchicine (45%) and corticosteroids (29%). Anti-interleukin-1 therapy and colchicine proved efficacy in CAPS and FMF patients, respectively. In addition, favorable responses demonstrated anti-interleukin-1 therapy in TRAPS, HIDS and colchicine-resistant FMF patients, as well as etanercept in TRAPS, HIDS and CRMO patients non-responsive to NSAIDs. Fifty seven% and 41% of patients were in complete and partial remission, respectively, at last visit. Conclusions AISs in children are associated with a broad spectrum of manifestations. A detailed history, thorough review of clinical manifestations and molecular testing of specific causative genes can provide early and accurate diagnosis and institution of efficient therapy. Disclosure of Interest None Declared

Results Fifty six patients were included: 17 CAPS, 4 TRAPS, 5 HIDS, 18 FMF, 6 CRMO, 2 SAPHO and 4 Behcet. The median follow-up period was 2 years (0-14 years). The male/female ratio was 20/36. The median age was 2.5 years at disease onset and 4 years at diagnosis. Family history was positive in 34% of patients. Clinical manifestations included fever (79%), mucocutaneous (61%), musculoskeletal (77%), ocular (34%), cardiorespiratory (12%), gastrointestinal (62%), neurological (41%) and genitourinary (2%) findings, lymphadenopathy with/or hepatosplenomegaly (16%) and growth impairment (27%). Seven patients presented severe manifestations: neonatal peritonitis (1 CAPS), pancreatitis (1 TRAPS), acute glomerulonephritis (1 FMF), complicated Henoch-Schonlein purpura (1 FMF), peritoneal adhesions with intestinal occlusion (1 FMF), periorbital pain (1 CRMO), and cerebral thrombosis (1 Behcet). One mutation was found in 93% of CAPS, and in all TRAPS patients. Two mutations were present in 11% of FMF, and in all HIDS patients. 43% of patients received colchicine, 23% steroids, and 54% biologics (Anakinra, Canakinumab, Etanercept). 57% of patients were in complete and 41% in partial remission.