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Objectives: Early antibiotic exposure influences the gut microbiota which is believed to be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). We aimed to investigate the association between systemic antibiotics in prenatal and early life and risk of JIA., Methods: We conducted a register-based cohort study including all children born in Norway from 2004 through 2012. The children were followed until 31 December 2020. Main exposures were dispensed antibiotics to the mother during pregnancy and to the child during 0-24 months of age. The outcome was defined by diagnostic codes indicating JIA. Multivariate logistic regression analyses were performed to estimate the association between antibiotic exposure and JIA., Results: We included 535 294 children and their mothers in the analyses; 1011 cases were identified. We found an association between exposure to systemic antibiotics during 0-24 months and JIA (adjusted OR (aOR) 1.40, 95% CI 1.24 to 1.59), with a stronger association for >1 course (aOR 1.50, 95% CI 1.29 to 1.74) vs 1 course (aOR 1.31, 95% CI 1.13 to 1.53). Subanalyses showed significant associations in all age periods except 0-6 months, and stronger association with sulfonamides/trimethoprim and broad-spectrum antibiotics. There was no association between prenatal antibiotic exposure and JIA., Conclusions: The novel observation of no association with prenatal antibiotic exposure and JIA suggests that the association between antibiotics in early life and JIA is unlikely to be confounded by shared family factors. This may indicate that exposure to antibiotics in early life is an independent risk factor for JIA., Competing Interests: Competing interests: SH: none declared, SA has received travel funding from Ferring pharmaceuticals., HS: none declared, KS: none declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The etiology of juvenile idiopathic arthritis (JIA) is poorly understood. This study investigated genetic and environmental factors and infant gut microbiota in a prospective birth cohort to assess disease risk., Methods: Data was collected from the All Babies in Southeast Sweden (ABIS) population-based cohort (n = 17,055), 111 of whom later acquired JIA (ABIS JIA ). Stool samples were collected at one year of age for 10.4%. To determine disease association, 16S rRNA gene sequences were analyzed, with and without confound adjustment. Genetic and environmental risks were assessed., Findings: ABIS JIA had higher abundance of Acidaminococcales, Prevotella 9, and Veillonella parvula and lower abundance of Coprococcus, Subdoligranulum, Phascolarctobacterium, Dialister spp., Bifidobacterium breve, Fusicatenibacter saccharivorans, Roseburia intestinalis, and Akkermansia muciniphila (q's < 0.05). Parabacteroides distasonis greatly increased the odds of later contracting JIA (OR = 6.7; 1.81-24.84, p = 0.0045). Shorter breastfeeding duration and increased antibiotic exposure compounded risk in a dose-dependent manner, especially in those with genetic predisposition., Interpretation: Microbial dysregulation in infancy may trigger or accelerate JIA development. Environmental risk factors have a stronger impact on genetically predisposed children. This study is the first to implicate microbial dysregulation in JIA at such an early age, with many bacterial taxa associated with risk factors. These findings provide opportunities for intervention or early screening and offer new insights into JIA pathogenesis., Funding: Barndiabetesfonden; Swedish Council for Working Life and Social Research; Swedish Research Council; Östgöta Brandstodsbolag; Medical Research Council of Southeast Sweden; JDRF-Wallenberg Foundation; Linköping., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to assess predictors of remission in children with juvenile idiopathic arthritis (JIA), treated with intra-articular corticosteroid injection (IACI) as monotherapy or in combination with methotrexate (MTX)., Methods: A retrospective study of 43 patients diagnosed with different JIA subtypes and followed-up at a tertiary center between 2000 and 2014. We included patients treated with IACI as monotherapy or in combination with MTX at onset or thereafter. We excluded patients treated with MTX as monotherapy or in combination with biologics. Patients were divided into two groups on the basis of assigned treatment. Primary outcomes were disease remission and duration. We performed descriptive analysis, bivariate analysis and cross-correlation analysis between variables. Statistically significant results (P value <0.05) were chosen as variables for multivariate analysis., Results: Median age of onset was 4.56 years (SD±3.85). Median time between disease onset and first IACI was 16.9 months (SD±34.7). We evaluated between time to remission in relation to age, time interval between onset and first IACI, time between onset and start of treatment with MTX, and time between first and second IACI. All of these were statistically significant (P value <0.05) in bivariate analysis, but time between onset and first IACI was the only statistically significant result, using multiple linear regression analysis. Therefore, in our study, 37 patients (86%) of patients went into remission on medication after a median disease duration of 48.8 months., Conclusions: We found that remission was related to time between onset and first IACI. Our predictive model showed that early IACI can be considered as a strong predictor of remission.

Background: Total knee arthroplasty (TKA) is rarely performed in patients under 21 years old, but the frequency of utilization of TKA in this population in the United States is not known. The purpose of this study was to evaluate trends in the use of TKA in patients <21 in the United States. Additionally, we aimed to determine the characteristics of these patients and the hospitals in which this procedure is performed., Methods: We retrospectively reviewed the Kids' Inpatient Database, a national weighted sample of all inpatient hospital admissions in the United States in patients <21 years of age. We used International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes to identify patients undergoing TKA from 2000 to 2019 and determine a primary diagnosis. Descriptive statistics were calculated using the appropriate sample weights., Results: The total weighted number of TKAs performed in patients <21 years from 2000 to 2019 was 1,535. There were 70.9% of TKAs performed for a primary diagnosis of tumor, and the use of TKA for malignant tumors has increased. In contrast, the use of TKA for inflammatory arthritis/juvenile idiopathic arthritis decreased significantly over the study period. The majority of TKAs were performed in urban teaching hospitals with a large bed size., Conclusion: Approximately 1,535 TKAs have been performed in patients <21 years from 2000 to 2019 in the United States. The majority of these procedures were performed for reconstruction after resection of a malignant tumor. The rate of TKA for inflammatory arthritis/juvenile idiopathic arthritis has decreased over the past two decades., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To determine whether there is a temporal association between arthritis and uveitis activity among children with juvenile idiopathic arthritis-associated uveitis (JIA-U)., Methods: Uveitis and arthritis data from patients with JIA-U age ≤21 years were collected from July 2013 to December 2019 at a tertiary care center. Arthritis activity was assessed at each rheumatology visit, and the primary outcome was the presence of active uveitis at ophthalmologic examination within 45 days of the rheumatology visit. Repeated-measures logistic regression was used to evaluate the temporal association between any uveitis activity within 45 days of arthritis activity. Models were adjusted for demographic-, disease-, and treatment-related factors., Results: A total of 98 patients were included: 81 (83%) female, 67 (69%) antinuclear antibody positive, 59 (60%) oligoarticular, and 13 (13%) enthesitis-related arthritis (ERA) subtypes. There were 1,229 rheumatology visits, with a median of 13 visits per patient (interquartile range 7-18). Concordance between arthritis and uveitis activity was observed 73% of the time (694 of 947). There was an independent temporal association between uveitis and arthritis activity (odds ratio 2.47 [95% confidence interval 1.72-3.54]; P < 0.01), adjusted for demographic and disease characteristics. Use of combination biologic and nonbiologic disease-modifying antirheumatic drugs, female sex, HLA-B27 positivity, and ERA and polyarticular (rheumatoid factor negative) subtypes were associated with decreased odds of active uveitis at any time point., Conclusion: In patients with JIA-U, there is a significant temporal association between arthritis and uveitis disease activity. These novel results suggest that an arthritis flare should prompt an expedited referral to the ophthalmologist., (© 2020 American College of Rheumatology.)

Objectives: JIA is the most common paediatric rheumatic disease, thought to be influenced by both genetics and the environment. Identifying environmental factors associated with disease risk will improve knowledge of disease mechanism and ultimately benefit patients. This review aimed to collate and synthesize the current evidence of environmental factors associated with JIA., Methods: Four databases (MEDLINE, Embase, Web of Science and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to January 2020. Study quality was rated using the Newcastle-Ottawa Scale. Pooled estimates for each environmental factor were generated using a random-effects, inverse-variance method, where possible. The remaining environmental factors were synthesized in narrative form., Results: This review includes 66 environmental factors from 39 studies (11 cohort and 28 case-control studies) over 45 years. Study sample sizes ranged from 41 to 1.9 million participants. Eight environmental factors from ten studies were meta-analysed. Caesarean section delivery was associated with increased JIA risk [pooled odds ratio (OR) 1.11, 95% CI: 1.01, 1.22]. Conversely, presence (vs absence) of siblings (pooled OR 0.60, 95% CI: 0.44, 0.81) and maternal prenatal smoking (pooled OR 0.70, 95% CI: 0.58, 0.84) were associated with decreased JIA risk., Conclusion: This review identifies several environmental factors associated with JIA and demonstrates the huge breadth of environmental research undertaken over five decades. We also highlight the challenges of combining data collected over this period due to limited between study comparability, evolution in healthcare and social practices, and changing environment, which warrant consideration when planning future studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Neutrophils are highly abundant in synovial fluid of rheumatic inflamed joints. In oligoarticular juvenile idiopathic arthritis (JIA), synovial fluid neutrophils have impaired effector functions and altered phenotype. We hypothesized that these alterations might impact the immunoregulatory interplay between neutrophils and T cells. In this study we analyzed the suppressive effect of neutrophils, isolated from blood and synovial fluid of oligoarticular JIA patients, on CD4 + T cells activated by CD3/CD28 stimulation. JIA blood neutrophils suppressed T cell proliferation but synovial fluid neutrophils from several patients did not. The loss of T cell suppression was replicated in an in vitro transmigration assay, where healthy control neutrophils migrated into synovial fluid through transwell inserts with endothelial cells and synoviocytes. Non-migrated neutrophils suppressed proliferation of activated CD4 + T cells, but migrated neutrophils had no suppressive effect. Neutrophil suppression of T cells was partly dependent on reactive oxygen species (ROS), demonstrated by impaired suppression in presence of catalase. Migrated neutrophils had reduced ROS production compared to non-migrated neutrophils. A proteomic analysis of transwell-migrated neutrophils identified alterations in proteins related to neutrophil ROS production and degranulation, and biological processes involving protein transport, cell-cell contact and inflammation. In conclusion, neutrophils in synovial fluid of children with JIA have impaired capacity to suppress activated T cells, which may be due to reduced oxidative burst and alterations in proteins related to cell-cell contact and inflammation. The lack of T cell suppression by neutrophils in synovial fluid may contribute to local inflammation and autoimmune reactions in the JIA joint., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arve-Butler, Mossberg, Schmidt, Welinder, Yan, Berthold, Król and Kahn.)

Background: The aetiology of juvenile idiopathic arthritis (JIA) is poorly understood. It has been shown that use of antibiotics is associated with JIA. However, whether the association is due to increased occurrence of infection in these individuals is unknown. The purpose of this investigation was to measure the association between number of infections and use of antibiotics during childhood with development of JIA., Methods: In ABIS (All Babies in Southeast Sweden) a population-based prospective birth cohort of 17,055 children, data were collected on infections and antibiotic exposure during pregnancy and childhood. 102 individuals with JIA were identified. Multivariable logistic regression analyses were performed, adjusting for confounding factors., Results: Exposure to antibiotics during the periods 1-12 months, 1-3 years and 5-8 years was significantly associated with increased risk for JIA. The odds of developing JIA were three times higher in those exposed to antibiotics during the first 3 years of life compared with those not exposed (aOR 3.17; 95% CI 1.11-9.03, p = 0.031), and more than twice as high in those exposed to antibiotics during the first 5 years of life compared with those not exposed (aOR 2.18; 95% CI 1.36-3.50, p = 0.001). The odds of developing JIA were 78% higher in those exposed to antibiotics during the first 8 years of life compared with those not exposed (aOR 1.78; 95% CI 1.15-2.73, p = 0.009). Occurrence of infection during fetal life or childhood showed no significant association with the risk of developing JIA, after confounder adjustment. The cumulative number of courses of antibiotics was significantly higher during childhood for the individuals who developed JIA (p < 0.001). Penicillins were more frequently used than non-penicillins, but both had an equal effect on the risk of developing JIA., Conclusions: Exposure to antibiotics early in life is associated with later onset of JIA in a large birth cohort from the general population. The relationship was dose dependent. These results suggest that further, more restrictive, antibiotic policies during the first years of life would be advisable., (© 2021. The Author(s).)

We studied the association of Enthesitis related arthritis (ERA) the most common variant of juvenile idiopathic arthritis (JIA) in Asians, with HLA-G and -E polymorphisms. HLA-G (14 bp Ins/Del rs371194629, +3142 rs1063320, +3187 rs9380142) and HLA-E (rs1264457, and rs2844724) polymorphisms were analyzed in 127 patients with ERA and 381 ethnically matched healthy controls with TaqMan 5'-nuclease assay using allele-specific fluorogenic oligonucleotide probes. HLA-G and -E polymorphisms were not found to be associated with susceptibility to ERA. HLA-G +3187 (rs9380142) G allele was associated with hip arthritis (Pc = 0.04, OR = 2.22, 95%CI = 1.07-4.63) and hip deformity (Pc = 0.02, OR = 2.51, 95%CI = 1.16-5.43). HLA-B*27 was positive in 91. HLA-E rs1264457 G and rs2844724 T alleles may be associated with B*27 positivity in ERA. Among HLA-G, -E haplotypes, frequency of -InsGAAC was significantly higher in patients than healthy controls (Pc = 0.003). In conclusion, HLA-G and HLA-E haplotype -InsGAAC may be associated with susceptibility to ERA and HLA-G +3187 rs9380142 A>G polymorphism may be a poor prognostic marker for progression to hip arthritis and deformity in ERA-JIA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. Depending on the number of joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. Greater understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease progression and remission to support stratification of patients to treatment pathways., (© 2021. The Author(s).)

Autoimmune diseases comprise a wide group of diseases involving a self-response of the immune system against the host. The etiopathogenesis is very complex involving disease-specific factors but also environmental factors, among which the diet. Maternal diet during pregnancy as well as early nutrition recently attracted the interest of the scientists as contributing to the immune programming. In this paper, we reviewed the most recent literature on the effect of maternal diet and early nutrition in modulating the immune system in a selected subset of autoimmune diseases: type 1 diabetes, celiac disease, inflammatory bowel disease, juvenile idiopathic arthritis and rheumatoid arthritis. Particularly, we focused our narrative on the role of maternal and perinatal nutrition in the epigenetic mechanisms underlying the auto-immune response. Maternal diet during pregnancy as well as breastfeeding and early nutrition play a big role in many epigenetic mechanisms. Most of the nutrients consumed by the mother and the infant are known exerting epigenetic functions, such as folate, methionine, zinc, vitamins B12 and D, fibers, casein and gliadin, and they were linked to gene expression changes in the immune pathways. Despite the common role of maternal diet, breastfeeding and early nutrition in almost all the autoimmune diseases, each disease seems to have specific diet-driver epigenetic mechanisms that require further investigations. The research in this field is opening new routes to establishing a precision nutrition approach to the auto-immune diseases.

Background: Observations among Israeli pediatric rheumatologists reveal that pediatric Juvenile Spondyloarthritis (JSpA) may present differently compared to patients from the United States (US). This study is aimed to compare the demographic and clinical variables of Israeli and US JSpA patients upon presentation., Methods: We performed a retrospective, cross-sectional, multicenter comparison of JSpA patients among 3 large Israeli pediatric rheumatology centers and a large US pediatric rheumatology center. Patients with diagnosis of Juvenile Ankylosing Spondylitis (JAS) and/or Enthesitis-related Arthritis (ERA) were included. The demographic, clinical and radiologic features were compared., Results: Overall 87 patients were included (39 Israeli, 48 US patients). Upon presentation, inflammatory back pain, sacroiliac joint tenderness and abnormal modified Schober test, were significantly more prevalent among Israeli patients (59% vs. 35.4, 48.7% vs. 16.7, and 41.2% vs. 21.5%, respectively, all p < 0.05), whereas peripheral arthritis and enthesitis were significantly more prevalent among US patients (43.6% vs. 91.7 and 7.7% vs. 39.6% in Israeli patients vs. US patients, p < 0.05). In addition, 96.7% of the Israeli patients versus 29.7% of the US patients demonstrated sacroiliitis on MRI (p < 0.001, N = 67). Less than one-third of the Israeli patients (32%) were HLA-B27 positive vs. 66.7% of US patients (p = 0.007)., Conclusion: Israeli children with JSpA presented almost exclusively with axial disease compared to US patients who were more likely to present with peripheral symptoms. HLA B27 prevalence was significantly lower in the Israeli cohort compared to the US cohort. Further studies are needed to unravel the genetic and possibly environmental factors associated with these findings.

X-linked agammaglobulinemia (XLA) is a rare genetic disease caused by a mutation in the Bruton tyrosine kinase (BTK) gene. It is characterized by a profound deficiency of B cells and a decrease in all classes of immunoglobulins (Ig). We report one case in a 3-year-old boy seen for recurrent acute otitis media, perineal abscess, oligoarthritis. The serum immunoglobulin (Ig) assay showed an IgG level of 0.6g/l. IgM and IgA are indosable. Marrow immunophenotyping showed an absence of precursor B less than 1%. Molecular biology confirmed Burton's disease (stop mutation, C37C) in exon 2 of the BTK gene. Treatment with intravenous immunoglogulin was started., Competing Interests: The authors declare no competing interests., (Copyright: Kaba Condé et al.)

Background: Inflammatory arthritis in children with Down syndrome (DS) was first described in 1984 and is now termed Down syndrome-associated arthritis (DA). Studies have shown that DA is under-recognized with a 19-month average delay in diagnosis. Additionally, most patients present with polyarticular, rheumatoid factor (RF) and anti-nuclear antibody (ANA) negative disease. Current therapies for juvenile idiopathic arthritis (JIA) have been used, but appear to be poorly tolerated, more toxic and less effective in patients with DA. There is currently no standardized approach to the assessment or management of DA. The objective of this study was to describe provider perspectives toward diagnostic and treatment approach of DA, to provide baseline information upon which to design future studies., Methods: An electronic survey, organized into sections regarding individual practices of assessment and treatment approach of DA, was sent to the Pediatric Rheumatology electronic list-serv. Survey responses were voluntary and results were analyzed by descriptive statistics., Results: Of 90 survey responses received, 89 were included in the analysis (one was a duplicate response). The respondents were mostly pediatric rheumatologist (94%), with greater than 10 years of experience (55%). The majority (64%) currently see 1-3 patients with DA. Most view DA as the same disease as JIA (73%), and the majority (63%) use a combination of history, exam and imaging to diagnose DA. The most ordered diagnostic tests are CBC (97%) and ESR (96%). The most used treatments include NSAIDs (94%) and methotrexate (91%) followed by anti-TNF agents (90%). Methotrexate is most administered by subcutaneous route (84%) at a dose of 15 mg/m 2 (56%). Oral corticosteroids were only used in 19% of the patients with DA., Conclusion: This is the first study to evaluate provider perspectives towards the diagnostic and treatment approach of DA. Most pediatric rheumatologists feel that DA and JIA are synonymous, and similar approaches to diagnosis are employed, utilizing history, physical exam, laboratory tests, and imaging modalities. DA is treated similarly to JIA with initiation of NSAIDs, disease-modifying anti-rheumatic drugs and biologic therapy. More research is needed to determine optimal screening and therapeutic approach specific to DA.

Objectives: Long-term safety and efficacy of adalimumab among patients with juvenile idiopathic arthritis (JIA) was evaluated through 6 years of treatment., Methods: Children aged 4-17 years with polyarticular JIA were enrolled in a phase III, randomised-withdrawal, double-blind, placebo-controlled trial consisting of a 16-week open-label lead-in period, 32-week randomised double-blind period and 360-week long-term extension. Patients were stratified by baseline methotrexate use. Adverse events (AEs) were monitored, and efficacy assessments included JIA American College of Rheumatology (JIA ACR) 30%, 50%, 70% or 90% responses and the proportions of patients achieving 27-joint Juvenile Arthritis Disease Activity Score (JADAS27) low disease activity (LDA, ≤3.8) and inactive disease (ID, ≤1)., Results: Of 171 patients enrolled, 62 (36%) completed the long-term extension. Twelve serious infections in 11 patients were reported through 592.8 patient-years of exposure. No cases of congestive heart failure-related AEs, demyelinating disease, lupus-like syndrome, malignancies, tuberculosis or deaths were reported. JIA ACR 30/50/70/90 responses and JADAS27 LDA were achieved in 66% to 96% of patients at week 104, and 63 (37%) patients achieved clinical remission (JADAS27 ID sustained for ≥6 continuous months) during the study. Attainment of JIA ACR 50 or higher and JADAS27 LDA or ID in the initial weeks were the best predictors of clinical remission. Mean JADAS27 decreased from baseline, 22.5 (n=170), to 2.5 (n=30) at week 312 (observed analysis)., Conclusions: Through 6 years of exposure, adalimumab was well tolerated with significant clinical response (up to clinical remission) and a relatively low retention rate., Competing Interests: Competing interests: DJL has served on speakers’ bureaus for Genentech and Bristol-Myers Squibb and on data and safety monitoring boards for Forest Research and the National Institutes of Health-NIAMS. Cincinnati Children’s Hospital Medical Center has received consulting fees from AbbVie, AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma and Genentech for the work of DJL.HIB has received speaker honoraria and consulting fees from AbbVie, AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, Takeda, UCB, Genentech, Lilly, Janssen, EMD Serono and R-Pharm; and has served on speakers bureaus for Genentech and Novartis.AOR has received consulting fees and speaker fees from AbbVie and Novartis.LJ has served as a consultant for OncoImmune and Novartis; has received unrestricted education grants from AbbVie; has received clinical trial support from AbbVie, Bristol-Myers Squibb and UCB Biosciences; and has served on a data and safety monitoring board for Bristol-Myers Squibb.KJ has nothing to disclose.DN has nothing to disclose.RM has received honoraria from AbbVie as a co-investigator during this clinical trial.CS has nothing to disclose.JFB has nothing to disclose.DE has received research grants, consulting fees and/or speakers fees from AbbVie.CG has nothing to disclose.GH has nothing to declare.IK-P has received consulting fees from AbbVie, Pfizer, Roche, CHUGAI, Novartis, SOBI and Novimmune.OYJ has nothing to disclose.VV has received speaker fees from AbbVie and Pfizer.EC has received speaker fees from AbbVie.CW has received research grants to her institution from Roche, Pfizer and GSK.IL and YS are full-time employees of AbbVie and may hold stock or stock options.AM is a professor of pediatrics at the University of Genoa, Italy, and has consultancy agreements with Janssen, Novartis and Pfizer. Prior to January 2019, AM was a scientific director of the Giannina Gaslini Hospital and performed consultancy activities on behalf of the Gaslini Institute for the following companies: AbbVie, Biogen, Boehringer, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, and R-Pharm.NR is a full-time employee of the Gaslini Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie, AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., ‘Francesco Angelini’, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma and Wyeth Pharmaceuticals. NR has served on speakers bureaus for Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche and Wyeth/Pfizer., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Harlequin Ichthyosis is the most severe variant of congenital autosomal recessive ichthyosis, associated with severe morbidity and potentially lethal in early life. At birth, patients present thick and plaque-like scales all over the body, with consequent cutaneous and extra-cutaneous complications, such as poor thermoregulation, recurrent infections, pain, electrolytes imbalance and joint contractures. Juvenile Idiopathic Arthritis usually manifests before the age of 16 years and persists for more than 6 weeks. The association between these two pathologies has been described in the literature as a very rare event, which creates diagnostic and therapeutic challenge., Case Presentation: We describe two patients affected by Harlequin Ichthyosis who early developed Juvenile Idiopathic Arthritis. Both patients were treated with retinoids, ibuprofen and long-acting intra-articular glucocorticoids; due to polyarticular involvement, one child was also treated with weekly oral methotrexate., Conclusions: The association between Harlequin Ichthyosis and Juvenile Idiopathic Arthritis is rare and the pathophysiological mechanism that binds them is still unknown. Nonetheless caregivers should be aware of the possible occurrence of Juvenile Idiopathic Arthritis at very early ages in children affected by Harlequin Ichthyosis.

Studies linking type of diet and juvenile idiopathic arthritis (JIA) have variable results and are inconsistent. This case shows an evolution which fulfilled the criteria of JIA, but was diagnosed as food allergy. Case: A seven-year old boy had fever, arthralgia, general malaise, headaches, abdominal pain and rashes. These symptoms were diagnosed as fever of unknown origin (FUO) and probable JIA. There was a stabbing pain in the right iliac fossa. An upper and lower endoscopy were performed and nodular ileocolitis was detected. A hypoallergenic diet was prescribed, in addition to mesalazine and oral corticosteroids. The patient was asymptomatic for 2.5 months and then relapsed with all symptoms after consuming dairy. This JIA case shows the diagnostic phases of food allergy: improvement and recurrence of symptoms with the reintroduction of the allergen (oral challenge=gold standard of food allergy). There is evidence that supports the existence of a gut-joint axis, where the luminal content triggers a series of immunologically mediated reactions that can cause systemic diseases such as J other connective tissue diseases. This case report adds reasonable evidence in support of food allergy as a cause of JIA.

Background: The oral microbiota has been implicated in the pathogenesis of rheumatoid arthritis through activation of mucosal immunity. This study tested for associations between oral health, microbial communities and juvenile idiopathic arthritis (JIA)., Methods: A cross-sectional exploratory study of subjects aged 10-18 years with oligoarticular, extended oligoarticular and polyarticular JIA was conducted. Control groups included pediatric dental clinic patients and healthy volunteers. The primary aim was to test for an association between dental health indices and JIA; the secondary aim was to characterize the microbial profile of supragingival plaque using 16S rRNA gene sequencing., Results: The study included 85 patients with JIA, 62 dental patients and 11 healthy child controls. JIA patients overall had significantly more gingival inflammation compared to dental patients, as evidenced by bleeding on probing of the gingiva, the most specific sign of active inflammation (p = 0.02). Overall, however, there was a trend towards better dental hygiene in the JIA patients compared to dental patients, based on indices for plaque, decay, and periodontitis. In the JIA patients, plaque microbiota analysis revealed bacteria belonging to genera Haemophilus or Kingella elevated, and Corynebacterium underrepresented. In poly JIA, bacteria belonging to the genus Porphyromonas was overrepresented and Prevotella was underrepresented., Conclusion: Increased gingival inflammation in JIA was independent of general oral health, and thus cannot be attributed to poor dental hygiene secondary to disability. The variation of microbial profile in JIA patients could indicate a possible link between gingivitis and synovial inflammation.

Turner syndrome (TS) results from a sex-chromosomal anomaly characterized by presence of one normal X chromosome and the loss of the second X-chromosome in phenotypic females. Autoimmunity has been recognized as one of the more prominent characteristics of TS. The risk of autoimmune diseases in patients with TS is approximately twice as high as in the general female population. The spectrum includes, Hashimoto's thyroiditis, coeliac disease (CD), type 1 diabetes (T1DM), alopecia areata, inflammatory bowel disease, juvenile rheumatoid arthritis and some cutaneous disorders as vitiligo and Halo nevus. This review will address the autoimmune disorders associated with TS, their pathophysiologic mechanisms and clinical characteristics.

Background: Musculoskeletal complications of Down syndrome (DS) are common but infrequently reported. The combination of ligamentous laxity and low muscle tone contributes to increased risk of a number of musculoskeletal disorders and a delay in acquisition of motor milestones. The primary aim of this study was to describe musculoskeletal anomalies reported in a national cohort of children with DS., Methods: This was an observational study. Children with DS, aged 0-21 years, were invited to attend a musculoskeletal assessment clinic conducted by a paediatric physician. Relevant musculoskeletal history and clinical findings were documented., Results: Over an 18-month period, 503 children with DS were examined (56% male). The median age was 8.1 years (0.6-19.2). Pes planus was almost universal, occurring in 91% of the cohort. A range of other musculoskeletal anomalies were observed, with inflammatory arthritis (7%) and scoliosis (4.8%) occurring most frequently after pes planus. Delay in ambulation was common; the median age to walk was 28 months (12-84)., Conclusion: Children with DS are at increased risk of a number of potentially debilitating musculoskeletal problems. These conditions can present in variable manners or be completely asymptomatic. Pes planus is common; therefore, early consideration of orthotics and lifelong appropriate supportive footwear should be considered. Delayed ambulation is frequently noted. A significant proportion of children with DS have arthritis; however, despite a high prevalence, it is often missed, leading to delayed diagnosis. An annual musculoskeletal assessment for all children with DS could potentially enable early detection of problems, allowing for timely multidisciplinary team intervention and better clinical outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128&#95;129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.

Juvenile idiopathic arthritis (JIA) is a chronic childhood arthritis. Its pathogenesis is very complicated, with the involvement of not only immune cells but various types of parenchymal cells, and is affected by both genetic and environmental predispositions. The clinical spectrum from inflammation to related conditions is largely mediated by cytokines including interleukin (IL)-6. Fluctuations in IL-6 and its related molecules can modulate the pathogenesis and the clinical presentation positively or negatively. The recent clinical impact of IL-6 blockade on JIA has begun a therapeutic paradigm shift. This review describes the characteristics of JIA, mainly focused on IL-6 with the current therapeutic perspective.

Autoantibody production occurs in juvenile idiopathic arthritis (JIA) and numerous other autoimmune diseases. In some conditions, the autoantibodies are clearly pathogenic, whereas in others the roles are less defined. Here we review various autoantibodies associated with JIA, with a particular focus on antinuclear antibodies and antibodies recognizing citrullinated self-antigens. We explore potential mechanisms that lead to the development of autoantibodies and the use of autoantibody testing in diagnosis and prognosis. Finally, we compare and contrast JIA-associated autoantibodies with those found in adults with rheumatoid arthritis (RA).

Background: To explore the effects of extracellular histones released by activated neutrophils on systemic-onset juvenile idiopathic arthritis (SoJIA), and to study the change of serum histone level between the active and remissive stage of SoJIA, then to clarify the role of serum histone in the pathogenesis of SoJIA., Methods: Twenty-six patients with SoJIA were recruited, and clinical informations were collected, and the serum histone was detected by ELISA. While neutrophils from normal children were incubated with the serum from the patients with SoJIA, also including incubated with FeCL3 and histone, the extracellular histone was detected, respectively; heparin was added to the above-mentioned groups to observe the changes of extracellular histone levels. The proportions of neutrophils, which released NETs, were calculated by confocal microscope., Results: The levels of serum histones in active SoJIA group (0.90 ± 0.90) were significantly higher than in remissive SoJIA group (0.17 ± 0.10) (P = 0.0009), and also higher than in control group (0.14 ± 0.09) (P = 0.246). Histone affects on clinical manifestations (including fever, rash, joint pain, liver and spleen enlargement, and serositis), except for joint pain. The proportions of neutrophils releasing NETs, that neutrophils were incubated with the serum from active SoJIA group, were 31.93% significantly higher than 12.32% from remissive SoJIA group (P < 0.0001). The proportions of neutrophils releasing NETs, that neutrophils were incubated with different concentration FeCl3 or with different concentration histones respectively, were positively correlated with the concentration of incubation; while heparins were added, NETs from neutrophils could be reduced effectively., Conclusions: The level of serum histone is positively correlated with the activity of SoJIA. Serum histone may be from NETs, which were released by activated neutrophils. Free iron can activate neutrophils to produce NETs, which may release histones, and histones can further promote NETs to be released, that results in a positive feedback loop of histones, and that may be one of the pathogenesis of acute SoJIA or MAS secondary to SoJIA. Histones maybe play one of important roles in the pathogenesis of SoJIA. Heparin can act on histones to prevent histone-induced inflammation., Trial Registration: ChiCTR-OOC-15006228. Registered 9 April 2015, http://www.chictr.org.cn/showproj.aspx?proj=10752.

Bilateral agenesis of the cruciate ligaments is a rare congenital anomaly. We report a unique case of a young girl who had congenital short femur and diagnosed with polyarticular juvenile idiopathic arthritis (JIA) and later discovered to have congenital absence of both anterior and posterior cruciate ligaments and meniscal dysplasia in both the knees when MRI was performed at 11 years of age. The MRI was performed to evaluate knee laxity and persistent symptoms despite medical management and multiple steroid injections for arthritis treatment. This patient is one of the youngest with congenital absence of both the cruciate ligaments to be treated with ACL reconstruction. We highlight the unique radiographic imaging manifestations of congenital cruciate ligament agenesis and emphasize the role of MRI to confirm and depict additional intraarticular abnormalities., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Juvenile idiopathic arthritis (JIA) is the most common inflammatory joint condition of childhood and represents seven JIA subtypes characterised by distinct clinical and laboratory variables. Genetic and environmental factors are known to influence JIA, although many unanswered questions remain. Measurement of health outcomes in JIA is imperative for both clinical practice and research. Patient-reported outcomes present particular challenges in paediatric rheumatology in view of the importance of collecting reports from both the child/young person and the parent. Another challenge is the need for continuity of outcome measurement across the paediatric-adult interface during the process of transition in terms of both measurement tools and the mechanisms in the system to facilitate tracking of the young person into adult care. Finally, the need for adults with JIA to be seen as a distinct group in adult rheumatology practice is important for both service provision and outcome research., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Background: Palindromic rheumatism is an idiopathic, periodic arthritis characterized by multiple, transient, recurring episodes. Palindromic rheumatism is well-characterized in adults, but has never been reported in pediatric populations. The aim of this study was to characterize the clinical features and outcomes of a series of pediatric patients with palindromic rheumatism., Methods: We defined clinical criteria for palindromic rheumatism and reviewed all clinical visits in three Pediatric Rheumatology centers in Israel from 2006through 2015, to identify patients with the disease. We collected retrospective clinical and laboratory data on patients who fulfilled the criteria, and reviewed their medical records in order to determine the proportion of patients who had developed juvenile idiopathic arthritis., Results: Overall, 10 patients were identified. Their mean age at diagnosis was 8.3 ± 4.5 years and the average follow-up was 3.8 ± 2.7 years. The mean duration of attacks was 12.2 ± 8.4 days. The most frequently involved joints were knees. Patients tested positive for rheumatoid factor in 20% of cases. One patient developed polyarticular juvenile idiopathic arthritis after three years of follow-up, six patients (60%) continued to have attacks at their last follow-up and only three children (30%) achieved long-term remission., Conclusions: Progression to juvenile idiopathic arthritis is rare amongst children with palindromic rheumatism and most patients continued to have attacks at their last follow-up. Longer follow-up periods are required to predict the long-term outcomes of pediatric patients with palindromic rheumatism.

In the past decades, we have gained important insights into the mechanisms of disease and therapy underlying chronic inflammation in juvenile idiopathic arthritis (JIA). These insights have resulted in several game-changing therapeutic modalities for many patients. However, additional progress still has to be made with regard to efficacy, cost reduction, minimization of side effects, and dose-tapering and stop strategies of maintenance drugs. Moreover, to really transform the current therapeutic strategies into personalized medicine, we need validated biomarkers to translate increased insights into clinical practice. In this article, we describe recent developments in JIA research and outline how clinical innovations need to go hand in hand with basic discoveries to really effect care for patients. Facilitating the transition from bench to bedside is crucial for addressing the major current challenges in JIA management. When successful, it will set new standards for a safe, targeted, and personalized medicine in JIA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Systemic juvenile idiopathic arthritis (sJIA) is considered as a polygenic autoinflammatory disease. The prominent systemic clinical features, the marked elevation of inflammatory markers, and the absence of autoantibodies make this disease very different from the other juvenile idiopathic arthritis (JIA) forms. Innate immune mechanisms appear to play a central role: the overproduction of inflammatory cytokines of innate immunity is a typical feature of sJIA. Increased understanding of the role of these cytokines has been translated into therapeutic approaches. Indeed, remarkable results have been observed with interleukin-1 (IL-1) and interleukin-6 (IL-6) inhibitors both in clinical trials and in real life. Other inhibitors of these cytokines will be available in the near future, thereby increasing the therapeutic armamentarium. A better understanding of the pathophysiology of sJIA is still needed to identify IL-1 or IL-6 responders, define a potential window of opportunity for early cytokine blockade, and identify a targeted treatment for macrophage activation syndrome. Additional therapeutic targets are needed for a small proportion of patients who do not respond to either IL-1 or IL-6 inhibition., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Juvenile idiopathic arthritis (JIA) is a heterogeneous condition and an important cause of acquired disability in children. Evidence supports early treatment to prevent future complications. This relies on prompt diagnosis, achieved by a high index of clinical suspicion and supportive evidence, including the detection of joint and or tendon inflammation. Ultrasound is a readily accessible, well-tolerated, safe and accurate modality for assessing joints and the surrounding soft tissues. It can also be used to guide therapy into those joints and tendon sheaths resistant to systemic treatments. Ultrasound imaging is highly operator dependent, and the developing skeleton poses unique challenges in interpretation with sonographic findings that can mimic pathology and vice versa. Ultrasound technology has been rapidly improving and is more accessible than ever before. In this article, we review the normal appearances, highlight potential pitfalls and present the key pathological findings commonly seen in JIA.

Objectives: Basic and epidemiological studies on rheumatic autoimmune diseases have suggested an association between vitamin D levels around time of birth and disease risk. The literature on vitamin D and juvenile idiopathic arthritis (JIA) is scarce. We hypothesized that low levels of 25-hydroxyvitamin D [25(OH)D] around time of birth would be associated with increased risk of oligo- or polyarticular JIA., Method: We conducted a case-cohort study of validated cases diagnosed with oligo- and polyarticular JIA (1993-2012) and controls matched on date of birth. Cases and controls were born in the period 1983-2010. Cases were diagnosed using international criteria. The concentration of 25(OH)D was assessed from neonatal dried blood spot (DBS) samples using high-sensitivity liquid chromatography tandem mass spectrometry (LC-MS/MS). Odds ratios (ORs) were calculated using conditional logistic regression and a two-way analysis of variance (ANOVA) was used to test for season and birth year 25(OH)D variations. A total of 300 matched pairs were included in the statistical analyses., Results: No significant association was found between levels of 25(OH)D and JIA risk in the adjusted model [OR (per 25 nmol/L increase) 1.2, 95% confidence interval (CI) 0.9-1.6, p = 0.2]. 25(OH)D levels were found to fluctuate significantly with season (p < 0.0001) and year (p < 0.0001). The median level of 25(OH)D was 34.4 nmol/L in cases and 31.5 nmol/L in controls., Conclusions: Our study does not support the hypothesis that a window of vulnerability exists around time of birth with regard to 25(OH)D levels and later JIA risk. Further studies should explore whether 25(OH)D levels during early pregnancy or infancy may influence JIA risk.

Background: The purpose of the study is to determine levels of total cholesterol (TC), low-density, and high-density lipoprotein fractions of cholesterol (LDLc and HDLc), in patients with juvenile idiopathic arthritis (JIA), and relate those to disease activity, overweight, and physical activity (PA), testing the hypothesis that the levels of cholesterol fractions are associated with inflammation as well as with overweight and low PA., Methods: Two hundred ten patients with JIA were included in this descriptive cross-sectional study. TC, LDLc, HDLc were measured, and associations with clinical disease activity (JADAS27), biomarkers of inflammation (myelo-related protein complex 8/14 (MRP8/14), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR)), body mass index (BMI), waist-to-height ratio (WtH ratio), and PA were explored., Results: Mean values for TC, LDLc, and HDLc in the patients were within the normal range for Danish Children. HDLc was negatively correlated with MRP8/14 (r = -0.343, CI -0.474 to -0.201, p < 0.0005) but was not related to overweight or PA. Neither TC nor LDLc showed any association with inflammation, overweight, or PA. MRP8/14 correlated positively with CRP, JADAS27 and WtH ratio (r = 0.277, CI 0.142 to 0.413, p = 0.001)., Conclusions: Levels of cholesterol fractions in patients with JIA were found within the normal range. Nonetheless, the level of HDLc was negatively associated with the level of the inflammatory marker MRP8/14, which is in accordance with the concept of inflammation as an important driver for premature development of atherosclerosis in JIA. WtH ratio (a measure of central fatness) was not associated to HDLc, but to MRP8/14, suggestive of central fatness as an additional driving factor for the chronic inflammation in JIA.

Background: To analyze the correlation of cytokines with clinical inflammatory indexes in systemic onset juvenile idiopathic arthritis (SOJIA)., Methods: A total of 30 active SOJIAs, 30 remission SOJIAs, and 20 normal controls were enrolled. The clinical inflammatory indexes such as tender joints counts, swelling joints counts, C-reactive protein, erythrocyte sedimentation rate, visual analogue scale (VAS), and disease activity score 28 (DAS28) were detected. The serum cytokines interleukin (IL)-17, IL-6, IL-21, interferon (IFN)-γ, and IL-4 levels were determined with enzyme-linked immunosorbent assay method. The correlation coefficients between these cytokines and two clinical indexes (VAS and DAS28) in the active SOJIA group were calculated with the Spearman's method., Results: The serum IL-17 and IL-6 levels in active SOJIA group were significantly increased compared with those in the remission SOJIA group and control group (p < 0.05), and the serum IL-21, IFN-γ, and IL-4 levels showed no obvious difference. In the active SOJIA group, the Spearman coefficients between IL-17 and DAS28, IL-17 and IL-6, IL-6 and DAS28, and between IL-17 and VAS were 0.686 (p = 0.000), 0.833 (p = 0.000), 0.633 (p = 0.000), and 0.524 (p = 0.003), respectively. There was no correlation between cytokines of IL-21, IFN-γ, and IL-4 and the clinical indexes of DAS28 and VAS. Furthermore, in the other two groups, none of the five cytokines exhibited an association with DAS28 or VAS., Conclusion: IL-6 and IL-17 were significantly correlated with DAS28 and VAS, and they might be considered as therapeutic targets for the treatment of SOJIA., (Copyright © 2016. Published by Elsevier B.V.)

The translation of basic insight in immunological mechanisms underlying inflammation into clinical practice of inflammatory diseases is still challenging. Here we describe how-through continuous dialogue between bench and bedside-immunological knowledge translates into tangible clinical use in a complex inflammatory disease, juvenile idiopathic arthritis (JIA). Systemic JIA (sJIA) is an autoinflammatory disease, leading to the very successful use of IL-1 antagonists. Further immunological studies identified new immune markers for diagnosis, prediction of complications, response to and successful withdrawal of therapy. Myeloid related protein (MRP)8, MRP14, S100A12, and Interleukin-18 are already used daily in clinic as markers for active sJIA. For non-sJIA subtypes, HLA-B27, antinuclear-antibodies, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein are still used for classification, prognosis or active disease. MRP8, MRP14, and S100A12 are now under study for clinical practice. We believe that with biomarkers, algorithms can soon be designed for the individual risk of disease, complications, damage, prediction of response to, and successful withdrawal of therapy. In that way, less time will be lost and less pain will be suffered by the patients. In this review, we describe the current status of immunological biomarkers used in diagnosis and treatment of JIA., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders characterized by chronic arthritis in children with unknown etiology. Although research evaluating environmental or early-life exposures in JIA is scarce, there are data to suggest that infections, smoking exposure, and lack of breastfeeding play a role. This case-control study investigated the association of selected environmental and early-life risk factors with the development of JIA., Methods: JIA cases were identified at a major pediatric rheumatology outpatient clinic. Each case was asked to identify up to 3 healthy playmates of similar age and same sex to serve as controls. Parents/caregivers of cases and controls completed a questionnaire on selected environmental and early-life exposures. Conditional logistic regression adjusted for age and socioeconomic status was used to determine the odds ratio (OR) for developing JIA with 95% confidence intervals (95% CIs) for the playmate-matched design., Results: Included in the study were 225 JIA cases and 138 controls. Compared to playmate-matched controls, preterm delivery (OR 1.8 [95% CI 1.2-2.7]) was associated with JIA. There was no association between JIA and household smoking or maternal prenatal smoking, breastfeeding, hospitalization with infection in the first year of life, daycare attendance before 6 years of age, household pets, or residential area prior to the onset of JIA., Conclusion: There was no association between the previously reported risk factors of smoking, early-life infection, or breastfeeding and development of JIA in this study. The association of preterm delivery with JIA needs to be further studied., (© 2016, American College of Rheumatology.)

The latest change in terminology from juvenile rheumatoid arthritis (JRA) to juvenile idiopathic arthritis (JIA), established by the International League of Associations for Rheumatology (ILAR), has resulted in some confusion for OMFS and other treating clinicians. JIA comprises a group of systemic inflammatory diseases that result in the destruction of hard and soft tissues in a single or multiple joints. In a significant number of patients, one or both temporomandibular joints (TMJ) are also involved. TMJ disease may be accompanied by pain, swelling, and limitation of motion, as well as mandibular retrognathism, open bite, and asymmetry. The purpose of this article is to provide a review, for the oral and maxillofacial surgeon, of the terminology, etiopathogenesis, diagnosis, and management of children with JIA., (Copyright © 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Alterations in the intestinal microbial flora have been linked with autoimmune diseases. Our objective was to analyse the composition of the faecal microbiome of children with new-onset juvenile idiopathic arthritis (JIA) compared to healthy controls, and to identify specific gut bacteria associated with JIA. Stool samples from patients were taken at the time of diagnosis of JIA. The microbiome profiles of samples of 30 children with JIA (mean age 6.2 years, 22 girls) were analysed with 16S region-based sequencing profiling and compared to the stool samples of healthy controls (n = 27, mean age 5.4 years, 18 girls). The proportion of bacteria belonging to the phylum Firmicutes was significantly lower in children with JIA [21 % (95 % confident interval [CI]: 17-25 %)] compared to controls [33 % (95 % CI: 26-41 %), p = 0.009]. Bacteria belonging to Bacteroidetes were significantly more abundant in JIA [78 % (95 % CI: 74-82 %)] than in control samples [65 % (95 % CI: 57-73 %), p = 0.008]. Shared operational taxonomic units (OTUs) between the groups revealed that genera Actinobacteria and Fusobacteria were present only in JIA patients and Lentisphaerae only in controls. In summary, faecal flora in JIA is characterised by a low level of Firmicutes and an abundance of Bacteroidetes, resembling the aberration reported in type 1 diabetes. We suggest that alterations in the intestinal microbial flora may challenge the mucosal immune system of genetically susceptible subjects predisposing to local proinflammatory cascades, thus contributing to the development of JIA.

Background: Incontinentia pigmenti (IP) is a rare genodermatosis with early prenatal lethality in affected males. Clinical manifestations are usually more exuberant in sporadic than in familial cases. Cutaneous manifestations occur in all sporadic cases and about 96% of familial cases. As well as the skin, other tissues arising from the neuroectoderm may be affected., Objectives: This study was designed to evaluate dermatologic, dental, neurologic, and ophthalmologic manifestations in patients with IP., Methods: Findings in IP patients and family members also diagnosed with IP in Porto Alegre, Brazil, during 2003-2012, were analyzed., Results: Thirteen children and seven relatives were diagnosed with IP; 38.4% of cases were familial, and 61.5% were sporadic. Mean ± standard deviation follow-up was 46.08 ± 39.47 months. Frequencies of 100% and 85.7% for dermatologic manifestations, 23.0% and 0% for neurologic manifestations, 62.5% and 71.4% for dental manifestations, and 11.1% and 42.8% for ophthalmologic manifestations were found in affected children and relatives, respectively. Associated diseases include Wilms' tumor, myasthenia gravis, Still's syndrome, and congenital hypothyroidism., Conclusions: These findings reinforce the heterogeneity of dermatologic findings and the numerous extracutaneous manifestations requiring a multidisciplinary approach. The follow-up of patients with IP is important in the detection of serious associated diseases. The relationships between these disorders and IP raise the need for additional longitudinal studies with longterm monitoring of these patients. The management of IP in clinical practice may benefit from early efforts to detect associated diseases., (© 2015 The International Society of Dermatology.)

Juvenile idiopathic arthritis, JIA, is a novel rheumatic disease in childhood introduced by the International League of Associations for Rheumatology. It is defined as a chronic, inflammatory disorder of unknown etiology, which is classified into seven categories; systemic-onset type, persistent and extended oligoarthritis, polyarthritis with rheumatoid factor negative, polyarthritis with rheumatoid factor positive, psoriatic arthritis, enthesitis-related arthritis and undifferentiated arthritis. As each category of JIA has different features in clinical phenotypes, precise subtyping is required for research and management. However, some modifications to the criteria might be helpful for getting better answers in diagnosis because of ethnical difference in prevalence and subtype distribution. Actually in Japanese population, a unique subset "B27-negative polyenthesitis" termed by Shichikawa should be included in enthesitis-related arthritis of JIA as a different type of enthesitis from B27-positive counterpart of spondyloarthritis in adulthood. Deep insights into the classification criteria will be needed for the better understanding of JIA.

Juvenile spondyloartrhritis is a group of multifactorial diseases in which a disturbed interplay occurs between the immune system and environmental factors on a predisposing genetic background, which leads to inflammation and structural damage of the target tissue. First symptoms of jSpA rarely involve the spine, while asymmetrical oligoarthritis of lower extremities, dactylitis, and peripheral enthesitis are much more common. There are many classification criteria for jSpA, but the majority of pediatric rheumatologists currently use the International League Against Rheumatism (ILAR) criteria according to which most patients with jSpA are classified into the enthesitis-related arthritis group of juvenile idiopathic arthritis. To meet these criteria, a patient should have arthritis and/or enthesitis, with two or more symptoms such as sacroiliac joint tenderness and/or inflammatory back pain, HLAB27 genotype, HLA B27 genotype-associated disease in a first- or second-degree relative, uveitis, and male sex with eight or more years of age. Therefore, diagnosis is most oft en made only based on clinical examination and medical history. Anti- nuclear antibodies (ANA), rheumatoid factor (RF), and HLA testing with B27, B7, and DR4 alleles are preferred. Since subclinical gut inflammation is present in many patients, it is recommended to check fecal calprotectin levels. In patients with signs of peripheral enthesitis it is warranted to perform power Doppler musculoskeletal ultrasound (PDUS), and in patients with signs of axial involvement radiographic and contrast-enhanced magnetic resonance imaging. Most patients are treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy, while in refractory cases with peripheral disease synthetic disease- modifying antirheumatic drugs (DMARDs), such as sulfasalazine, are used. In patients with axial involvement, biological DMARDs such as adalimumab, infliximab, and etanercept are obligatory. Although a number of studies gave us a good insight into the disease pathogenesis, the response to treatment and prognosis are still difficult to predict.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disorder in children and one of the most common causes of part-time or long-term disability. The term juvenile idiopathic arthritis defines the main characteristics of the disease: joint inflammation of unknown origin manifested before the 16th birthday and lasting for more than six weeks. JIA is very rare in infancy, with highest frequency in preschool age. It is not a single disease, but a group of disorders with some common features of different immunopathogenesis and with different clinical manifestations. According to the revised International League of Associations for Rheumatology (ILAR) criteria, JIA is classified into 8 subtypes, but this classification is still a “work in progress“ because with new knowledge gained in genetics and immunology, the classification will obviously have to be changed and refined. New research of the disease pathogenesis is the basis for the development of new and better treatments for JIA. The goal of such treatments is not just to relieve pain, but also to control inflammation and stop irreversible joint damage and long-term disability. Biological agents have significantly improved the disease prognosis.

Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease affecting children aged less than 16 years, characterized by chronic synovitis, cartilage damage, and bony erosions mediated by matrix metalloproteinases (MMPs), mainly MMP-1 and MMP-3. The purpose of this study was to investigate MMP-1 and MMP-3 gene polymorphisms in patients with JIA, the role of genes in susceptibility to JIA, and their associations with JIA activity and prognosis. Case-control study included 100 patients diagnosed with JIA, according to the criteria of the International League of Associations for Rheumatology (ILAR), and 100 healthy children, age and sex matched, as controls. The MMP-1 (-1607 1G/2G) and MMP-3 (-1171 5A/6A) polymorphisms were screened by polymerase chain reaction-restriction fragment length polymorphism. The serum levels of MMP-1 and MMP 3 were measured by enzyme-linked immunosorbent assay. There were significant differences between patients with JIA and control groups regarding the genotype and allele frequencies distributions of both MMP-1 1G/2G and MMP-3 5A/6A polymorphisms. The haplotype 2G-6A, which carries the abnormal alleles, showed higher frequencies in patients with JIA than in controls (OD = 2.8, P = 0.002). The prevalence of MMP-1 2G and 6A allele for MMP-3 polymorphism was found to be significantly associated with persistent oligoarticular, rheumatoid factor (RF)-positive polyarthritis, and systemic JIA groups. There were significantly increased serum levels of MMP-1 and MMP-3 associated with 2G/6A haplotype in the patient group, especially with the polyarticular RF (+ve) group than in other groups and the control group. MMP-1 and MMP-3 haplotypes could be useful genetic markers for JIA susceptibility and severity in the juvenile Egyptian population. Moreover, our data further support the use of serum MMP-3 and MMP-1 as specific markers of disease activity in JIA., (© 2015 International Union of Biochemistry and Molecular Biology.)