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OBJECTIVES: Observational studies report mixed findings regarding the association between vitamin D and JIA incidence or activity, however such studies are susceptible to considerable bias. Since low vitamin D levels are common within the general population and easily corrected, there is potential public health benefit in identifying a causal association between vitamin D insufficiency and JIA incidence. To limit bias due to confounding and reverse causation we examined the causal effect of the major circulating form of vitamin D, 25-(OH)D, on JIA incidence using Mendelian randomization (MR).METHODS: In this two sample MR analysis we used summary level data from the largest and most recent genome wide association study (GWAS) of 25-(OH)D levels (sample size 443,734), alongside summary data from two JIA GWASs (sample sizes 15,872 and 12,501), all from European populations. To test and account for potential bias due to pleiotropy we employed multiple MR methods and sensitivity analyses.RESULTS: We found no evidence of a causal relationship between genetically predicted 25-(OH)D levels and JIA incidence (OR 1.00, 95% CI 0.76-1.33 per standard deviation increase in standardised natural-log transformed 25-(OH)D levels). This estimate was consistent across all methods tested. Additonally there was no evidence that genetically predicted JIA causally influences 25-(OH)D levels (-0.002 standard deviation change in standardised natural-log transformed 25-(OH)D levels per doubling odds in genetically predicted JIA, 95% CI -0.006-0.002).CONCLUSION: Given the lack of a causal relationship between 25-(OH)D levels and JIA, population level vitamin D supplementation is unlikely to reduce JIA incidence.

Objective Juvenile- and adult-onset ankylosing spondylitis (AS) are subtypes of AS that may have different clinical outcomes. We compared cohorts of juvenile-onset AS and adult-onset AS in terms of clinical characteristics, clinical outcomes, proceeding to AS-related orthopedic surgery, and type of orthopedic surgery. Methods A retrospective cohort study was conducted of all AS patients attending a teaching hospital. Demographics, clinical parameters, and history of AS-related orthopedic surgery to the spine, root, or peripheral joints were recorded. Differences between surgery for juvenile- and adult-onset AS patients, and effects of covariates were assessed using logistic regression and survival analyses. Results A total of 553 AS patients were studied: 162 juvenile-onset AS and 391 adult-onset AS cases. After adjusting for significant covariates, adult-onset AS cases were less likely to proceed to surgery (odds ratio [OR] 0.31, P

OBJECTIVE: To investigate the association of NLRP3, NOD2, MEFV, and PSTPIP1, genes that cause 4 of the autoinflammatory hereditary periodic fever syndromes (HPFS), with juvenile idiopathic arthritis (JIA). METHODS: Fifty-one single-nucleotide polymorphisms (SNPs) across the 4 loci were investigated using MassArray genotyping in 950 Caucasian patients with JIA living in the UK and 728 ethnically matched healthy controls. RESULTS: Prior to Bonferroni correction for multiple testing, significant genotype associations between 6 SNPs in MEFV and JIA were observed and, in subgroup analysis, associations between 12 SNPs across all 4 loci and the subgroup of patients with psoriatic JIA were found. After Bonferroni correction for multiple testing, 2 genotype associations remained significant in the subgroup of patients with psoriatic JIA (MEFV SNP rs224204 [corrected P = 0.025] and NLRP3 SNP rs3806265 [corrected P = 0.04]). CONCLUSION: These findings support the use of monogenic loci as candidates for investigating the genetic component of complex disease and provide preliminary evidence of association between SNPs in autoinflammatory genes and psoriatic JIA. Our findings raise the interesting possibility of a shared disease mechanism between the HPFS and psoriatic JIA, potentially involving abnormal production of interleukin-1beta.

Background/Purpose: Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory bone disease occurring primarily in children and adolescents. Delays in referral and diagnosis may lead to prolonged courses of antibiotics with in-patient care, substantial radiation exposure from multiple plain radiographs or bone scans and bone biopsies which may be repeated. Methods: Children (aged less than 18 years) diagnosed with CRMO between January 2005 and December 2012, who were reviewed at Bristol Royal Hospital for Children were included; their clinical notes reviewed, laboratory, histopathology and radiology data were extracted. We retrospectively applied the Bristol criteria for diagnosis (table 1). Table 1. Bristol diagnostic criteria for CRMO a Typical clinical findings include bony pain with or without localised swelling. Absence of significant local or systemic features of inflammation or infection. b Typical radiological findings constitute: plain x-rays showing a combination of lytic areas, sclerosis and new bone formation or preferably STIR MRI showing bone marrow oedema +/− bone expansion, lytic areas and periosteal reaction. The presence of typical clinical (a) and radiological findings (b) in more than one bone (or clavicle alone) without significantly raised inflammatory markers OR Typical clinical and radiological findings in one bone plus inflammatory changes (plasma cells, osteoclasts, fibrosis or sclerosis on bone biopsy with no bacterial growth. Results: Forty one patients (Female: Male ratio 31:10) were diagnosed as CRMO and assessed at the Bristol centre over the 8 year period. The onset of symptoms occurred at a median of 9 years with a delay in diagnosis with a median of 15 months (range 0–92). Initial plain radiograph was abnormal in 28 out of 36 patients; whole body MRI (WB-MRI) detected lesions in seven of the patients with normal plain radiograph. 162 lesions were identified by imaging, of which, 47 were asymptomatic and detected only by MRI. After imaging, only ten patients (24%) had a solitary lesion (six of which were clavicle alone). From the data, diagnostic criteria were developed. Using the proposed criteria retrospectively, thirty-four children could have potentially been diagnosed by criterion 1, with 6 children requiring a biopsy (criterion 2) for diagnosis, either for a solitary lesion not clavicle or atypical features such as age. Bone biopsies in our cohort had been repeated in a third of patients prior to referral. Thirteen children completed at least one year of pamidronate treatment with MRI available both before and after treatment on eleven of these. After a year of pamidronate therapy, 71% of lesions improved and 29 % remained stable on MRI scans. Around 20%–30% patients having pamidronate therapy will continue to have troublesome symptoms. Conclusion: We suggest that using the Bristol diagnostic criteria (table 1) with an experienced clinician may obviate the need for biopsy in some patients. Pamidronate was found to be a useful second-line agent with objective MRI evidence of benefit.

Background/Purpose: Lupus nephritis (LN) is a serious complication of juvenile-onset systemic lupus erythematosus (JSLE). Current treatments include longterm immunosuppressants with significant side effects. There is a need to identify targets for more effective therapies. Toll-like receptors (TLRs) perform an important role in the innate immune response by recognising conserved molecules associated with pathogens. Previous studies have suggested a role for TLR7 and TLR9 in lymphocytes in the pathogenesis of SLE. Podocytes are specialised cells forming an important part of the glomerular filtration barrier. Biopsies from LN patients have demonstrated higher TLR7 and TLR9 expression in glomeruli compared with controls and suggest that these TLRs are localised to podocytes. We hypothesise that stimulation of TLR7 and/or TLR9 in podocytes, acting via nuclear factor kappa B (NFkB), leads to cellular damage and resultant kidney disease. This research aims to examine the role of TLR7 and TLR9 in podocytes to identify potential targets for more effective therapies of lupus nephritis. Methods: Conditionally-immortalised human podocyte cell lines were cultured to examine expression of TLRs and the effects of their activation on the NFkB pathway and cell proliferation. Reverse transcriptionquantitative polymerase chain reaction (RT-qPCR) and sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE) with Western blotting were used to detect TLR7 and TLR9 expression at the mRNA and protein level respectively. The effects of lipopolysaccharide (LPS), an inflammatory stimulus, on TLR expression were examined. Podocytes were stimulated with imiquimod, a specific TLR7 agonist and CpG oligodeoxynucleotide (ODN) 2216, a specific TLR9 agonist. Phosphorylation of NFkB pathway components was assessed with Western blotting and a cell proliferation assay used to estimate cell survival following treatments. The effects of treatment with TLR agonists in combination with dexamethasone were also examined. Results: Treatment of podocytes with LPS was associated with increased expression of TLR7 at both mRNA and protein levels whereas there was comparatively little change in TLR9. Exposure of the cells to imiquimod or CpG ODN 2216 increased phosphorylation of NFkB. Initial results from the cell proliferation assay suggested lower levels after imiquimod or CpG ODN 2216 treatment for 24 hours. Since podocytes are terminally differentiated this implies reduced cell numbers or lower metabolic activity. Exposure of the podocytes to dexamethasone was associated with lower expression of TLR7 and TLR9 at the mRNA level. There was preliminary evidence of less phosphorylation of NFkB when cells were treated with dexamethasone prior to TLR agonists compared with the latter alone. Conclusion: This study suggests that podocytes express TLR7 and TLR9. Agonists of these receptors have effects on intracellular signalling. If confirmed through ongoing work, the TLR-NFkB pathway in kidney cells may be a potential target for novel therapies in lupus nephritis.

Background/Purpose: Juvenile systemic granulomatous disease (JSGD), also known as Blau syndrome, is a dominantly-inherited autoinflammatory disorder associated with gain-of-function mutations in the NOD2 gene. The aim of this study was to determine whether patients with JSGD and uveitis have a specific ocular phenotype. Methods: Clinical and imaging data were collected retrospectively from patients attending the Regional Combined Paediatric Rheumatology and Ocular Inflammatory Service, Bristol Eye Hospital. General demographic information, laterality of the uveitis, age at onset, anatomical classification and course of the uveitis, clinical phenotype, and specific NOD2 mutation were recorded for each patient. All data were recorded in a database designed in Microsoft® Access®. Statistical analysis was performed using SPSS 20.0 (Cary, NC). Results: Seventeen eyes from 9 patients (5 males; 4 females) were included in the study. Mean age at the disease onset was 15 months; range 1–84 months. Eight patients had bilateral uveitis. Anterior uveitis was present in five eyes, intermediate uveitis in 2 eyes and there were 10 eyes with panuveitis, manifesting as multifocal choroiditis. Appearance of optic disc included indistinct disc margins in 6 eyes, optic nerve head palor in 6 eyes and optic disc vessels sheathing in 4 eyes. Fundal appearance included peripapillary hypo/hyperpigmention in 13 eyes accompanied with characteristic peripapillary nodular excrescences. Among NOD2 mutations, the p.R334W was the most commonly detected (n: 4 cases) and three patients carried novel variants, the p.E338D and p.D390V variants in one patient, and the p.H520Y and p.Q809K variants in two different patients. Conclusion: Chronic bilateral panuveitis and a nodular peripapillary appearance in childhood onset uveitis are characteristic features of JSGD, which support the need for an appropriate genetic NOD2 analysis.