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Background There has been a significant increase in financial support of clinical research by the pharmaceutical industry. Methods We performed a comprehensive systematic literature review to determine whether there is publication bias for rheumatoid arthritis (RA) studies between industry-funded and non-industry funded randomized controlled trials (RCTs), and between RCTs with positive results (PRs) and those with negative results (NRs) of FDAapproved biological and small molecule drug therapy for RA. Each RCT was classified as having either a PR or a NR, and as having received commercial funding or not. Results Most (297/349, 85.18%) of the RCTs were commercially funded. There was no significant difference in PRs or association with publication between commercially and noncommercially funded RCTs. Sample size was significantly larger in commercially funded RCTs and in those with PRs, and it was the only significant parameter that predicted publication in higher impact factor journals in the field of RA. Conclusion There is no significant association between commercial funding and the publication of positive results or the publication of an RCT in higher impact factor journals.

Background:The “European League Against Rheumatism” and “American College of Rheumatology” 2019 (EULAR/ACR-19) criteria for the diagnosis of Systemic Lupus Erythematosus (SLE) were recently published, with the stated goal of maintaining the level of sensitivity and raising the level of specificity for classification of SLE in adults.Objectives:We aimed to examine the function of the new EULAR/ACR-19 criteria in a population of children and compare them to the SLICC-12 and ACR-97 criteria.Methods:In this multicenter study the charts of jSLE patients from three tertiary medical centers were reviewed and compared to patients with non-jSLE diagnosis. Pediatric rheumatologists, blinded to the original diagnosis, reviewed and diagnosed all cases. Pediatric patients’ clinical and laboratory data were retrospectively extracted and then examined with regard to how they met the new and old criteria.Results:Included were 225 patients (112 jSLE, 113 non-SLE). When applied to juvenile SLE classification, the sensitivity of the new EULAR/ACR-19 criteria was 0.96 (0.9-.0.99) and the specificity was 0.89 (0.82-0.94). These were comparable to the Systemic Lupus International Collaborating Clinics (SLICC) criteria. The sensitivity of the EULAR/ACR-19 criteria improves over time and was 0.83 twelve months following disease onset, reaching 0.96 after longer than 24 months.Conclusion:Among a cohort of jSLE patients, sensitivity of the new EULAR/ACR-19 criteria was found to be high and specificity may have improved slightly compared to the SLICC-12 criteria. We support the use of the new classification criteria for pediatric patients in future jSLE studies, but it should be noted that its specificity is lower than for adults.ACR-97SLICC-12EULAR/ACR-19Sensitivity (95% CI)0.79 (0.70-0.86)0.96 (0.9-0.99)0.96 (0.9-.0.99)Specificity (95% CI)0.94 (0.88-0.97)0.85 (0.77-0.91)0.89 (0.82-0.94)Accuracy (95% CI)0.86 (0.81-0.9)0.9 (0.86-0.94)0.92 (0.88-.0.96)Positive Likelihood Ratio (95% CI)12.7(6.1-26.2)6.35(4.1-9.9)9.0 (5.3-15.4)Negative Likelihood Ratio (95% CI)0.23(0.16-0.33)0.05(0.02-0.12)0.05(0.02-0.12)Diagnostic odds ratio (95% CI)55.5(22.80-135.0)120.85(43.0-340.0)180.1(61.3-529.4)References:[1]Smith EMD, Lythgoe H, Midgley A, Beresford MW, Hedrich CM. Juvenile-onset systemic lupus erythematosus: Update on clinical presentation, pathophysiology and treatment options. Clin Immunol 2019 published on December 2019. doi: 10.1016/j.clim.2019.108274[2]Massias JS, Smith EMD, Al-Abadi E, Armon K, Bailey K, Ciurtin C, et al. Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups. Lupus 2020;29(5):474–81.[3]Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725[4]Petri M, Orbai AM, Alarcõn GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012 Aug;64(8):2677-86[5]Hartman EAR, van Royen-Kerkhof A, Jacobs JWG, Welsing PMJ, Fritsch-Stork RDE. Performance of the 2012 Systemic Lupus International Collaborating Clinics classification criteria versus the 1997 American College of Rheumatology classification criteria in adult and juvenile systemic lupus erythematosus. A systematic review and meta-an. Autoimmun Rev. 2018;17(3):316–22.[6]Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol 2019;71(9):1400–12.Disclosure of Interests:None declared

To describe a cohort of pediatric patients diagnosed with periodic fever aphthous stomatitis, pharyngitis and adenitis (PFAPA) and familial Mediterranean fever (FMF) and compare them with children diagnosed solely with PFAPA (sPFAPA).Clinical, laboratory, and genetic data of all pediatric patients diagnosed with sPFAPA or PFAPA/FMF were retrospectively collected from 2 primary Israeli medical referral centers and compared.Of 270 patients with PFAPA, more than one-half were of Mediterranean ancestry. Among patients with PFAPA, 51 (18.9%) also were diagnosed with FMF (PFAPA/FMF). Genetic data on the 9 most common MEFV variants were available for 45 children (88%) in the PFAPA/FMF group. Two variants were found in 15 children (33.3 %), 1 variant was found 27 patients (60%), and 3 patients (6.6%) had no variants. Abdominal pain, myalgia, and arthralgia each were more commonly reported in the PFAPA/FMF group compared with the sPFAPA group (90% vs 49% [P .0001]; 46% vs 23% [P = .02]; and 30% vs 17% [P = .049], respectively). Colchicine was more commonly prescribed for the PFAPA/FMF group compared with the sPFAPA group (82% vs 29%; P .0001), but alleviation of PFAPA symptoms with colchicine was similar between groups (75% vs 63%; P = .23).We show a strong association between 2 common autoinflammatory syndromes, PFAPA and FMF, in patients from Mediterranean ancestry. Clinicians should be aware that presentation of 1 disease may clinically evolve into another. The association between PFAPA and FMF poses the question similar pathogenesis and genetic influence of the MEFV gene on PFAPA.

Objective We assessed publication bias in the field of systemic lupus erythematosus (SLE) by conducting a search of randomized, controlled trials (RCTs) on SLE therapies that had been published over the past 45 years. Our aim was to assess a potential publication bias by determining whether RCTs reporting positive results, RCTs with placebo arms, biologics RCTs, and industry-funded RCTs are more likely to be published in journals with higher impact factors (IFs). Methods We conducted a systematic review of all RCTs registered in PubMed between 1 January 1975 and 1 November 2016. Each RCT was classified as having a positive result (PR) or a negative result (NR). The IF of each journal was determined for the year of publication. Results Our search yielded 233 relevant RCTs. There was no significant difference in IFs between studies with NRs and those with PRs or between studies that were financially supported by commercial companies compared to studies that were not. However, there was a significant correlation between sample size and the journal's IF. Conclusions IF scores of RCTs in the field of SLE are influenced by sample size and not biased by either a tendency to report PRs or by being funded by pharmaceutical companies or any other commercial sources.

Eosinophilic fasciitis (EF) is a rare connective tissue disease characterized by erythema, edema and myalgia with induration and thickening of the skin and soft tissue, especially subcutaneous fascia. Laboratory findings usually show peripheral eosinophilia, and full-thickness wedge biopsy is essential to establish the diagnosis. Corticosteroids are effective and remain the standard therapy for EF, although some patients may improve spontaneously. In this article we report a case of a 17 years old male who has been diagnosed with EF 2 years after bone marrow transplantation and review the clinical manifestations, pathology, diagnosis, differential diagnosis, and treatment of EF.

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.

Background This study examined whether the comic book Neta and the Medikidz Explain JIA would improve disease-related knowledge and treatment adherence among patients with juvenile idiopathic arthritis (JIA). Methods In this prospective cohort study, JIA patients answered 20 multiple-choice knowledge questions about their disease, before and after reading the comic book. Demographic, clinical, health-related quality of life and adherence data were recorded and correlated to the responses. Results We studied 61 patients with a mean age of 14 ± 3.3 (range 8–18) years, 67% female, 83% Jewish and 17% non-Jewish. Thirty-nine percent had oligoarthritis, 13% systemic, 32% polyarthritis 11% psoriatic and 5% enthesitis-related type JIA. The disease was active in 46%, 40% were treated with biologics/disease modifying anti-rheumatic drugs, and 34% were in remission on medication. Among the 53 patients who completed before and after quizzes, average score increased from 63 to 80% (P

To examine publication outcomes of neonatology abstracts presented at Pediatric Academic Society (PAS) meeting, and to analyze variables affecting publication.All neonatology studies accepted for presentation (oral or poster) at 2008 PAS meeting were identified. A biphasic manual PubMed search of published articles was performed using a pre-designed algorithm.A total of 1078 neonatology abstracts were presented at the meeting, among them 481 (44.62%) published by 2016. Abstracts presented orally versus posters (56.11 versus 42.32%; P0.001) and basic science versus clinical abstracts (53.08 versus 40.2%; P0.001) were more likely to be published. Positive or negative results of a study or its sample size did not predict rates of publication.Less than half of the abstracts presented at the PAS meeting were published within 8 years. Oral presentations were more likely to be published than posters.Journal of Perinatology advance online publication, 6 April 2017; doi:10.1038/jp.2017.46.

The proinflammatory activity of IL-17–producing Th17 cells has been associated with the pathogenesis of several autoimmune diseases. In this article, we provide direct evidence for a role of IL-17 in the pathogenesis of systemic lupus erythematosus (SLE). The induction of SLE by pristane in IL-17–sufficient wild-type mice did not occur in IL-17–deficient mice, which were protected from development of lupus autoantibodies and glomerulonephritis. The protection from SLE in IL-17–deficient mice was associated with a reduced frequency of CD3+CD4−CD8− double-negative T cells and an expansion of CD4+ regulatory T cells, and did not depend on Stat-1 signaling. These data affirm the key role of IL-17 in the pathogenesis of SLE and strengthen the support for IL-17 blockade in the therapy of SLE.

Objective The American College of Rheumatology (ACR) and the Association of Rheumatology Health Professionals (ARHP) Annual Scientific Meeting is an important forum for early dissemination of novel ideas. However, unlike published studies in peer-reviewed journals, reviewers select abstracts based solely on a general summary of the research. Analyses of the scientific impact and the publication record of the ACR/ARHP Annual Meeting have not been previously described. This study characterizes publication trends and outcomes associated with abstracts presented at the ACR/ARHP Annual Scientific Meeting. Methods We identified all abstracts accepted for oral or poster presentation at the 2006 ACR/ARHP Annual Scientific Meeting. Using a defined search algorithm, we conducted a manual PubMed search for each accepted abstract, which was repeated by a custom computerized search, and analyzed the resulting journal title, impact factor, and time to publication. Results A total of 2,149 abstracts were analyzed. The overall publication ratio was 59.1%. The mean ± SD time from abstract presentation to publication was 18.2 ± 15.2 months with a mean ± SD impact factor of 5.61 ± 4.20. Overall, studies presented in oral format were significantly more likely to be published than poster presentations (P < 0.0001). The average time to publication was significantly shorter for basic science studies than clinical research studies (P < 0.0001). The average journal impact factor of published studies presented in oral format was significantly higher than those presented as posters (P < 0.0001). Conclusion These results reflect high research productivity with a publication ratio of approximately 60% for abstracts presented at the 2006 Annual Scientific Meeting.

Folate supplementation is widely accepted and utilized for the prevention of adverse events in juvenile idiopathic arthritis (JIA) patients who are treated with methotrexate. Despite the widespread use of folate supplementation, there is a lack of convincing evidence to support the role of folate in the enhancement of methotrexate efficacy and the prevention of methotrexate-related adverse events. In order to understand current practices used by experts, we surveyed 214 pediatric rheumatologists around the globe. Seventy-one unique folate supplementation regimens were reported for this study. Results indicated that folate supplementation (either in the form of folic acid or folinic acid) is inconsistent and highly variable within the United States as well as between the United States and other countries. This level of variability is often associated with lack of evidence and emphasizes the need for well-designed clinical trials to support a rational folate supplementation regimen in patients with JIA who are treated with methotrexate.

To assess the practice patterns of pediatric rheumatology and infectious diseases subspecialists in the diagnosis and treatment of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. An online survey assessing diagnostic and treatment approaches was sent to 424 members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) and 980 members of the Pediatric Infectious Disease Society (PIDS). 277 physicians (123 from CARRA and 154 from PIDS representing 21% of the total membership) completed the survey. To diagnose PFAPA, most respondents agreed that patients must have the following features of the diagnostic criteria: stereotypical fever episodes (95%), asymptomatic intervals between episodes (93%), and normal growth and development (81%). However, 71% of the respondents did not require age of onset

To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes.This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage.The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups.We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered.

BACKGROUND: Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website.OBJECTIVES: This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis.METHODS: Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy.RESULTS: FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The "signal" in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical.CONCLUSION: There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias).

Background and objective Although various biological agents are in use for polyarticular juvenile idiopathic arthritis (pJIA), head-to-head trials comparing the efficacy and safety among them are lacking. We aimed to compare the efficacy and safety of biological agents in pJIA using all currently available randomized withdrawal trials (wRCTs). Methods A systematic search of MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov was performed. Eligible wRCTs: patients with pJIA where a biological agent was compared with another biological agent or placebo. Efficacy was evaluated using disease flare as a measure. Adverse events (AEs) and serious AEs were evaluated. Network meta-analysis compared biological agents based on a (empirical Bayes) mixed-effects logistic regression model that combines statistical inference from both direct and indirect comparisons of the treatment effects between biological agents. Results Of 496 references identified, five wRCTs were included—abatacept, adalimumab, anakinra, etanercept, and tocilizumab, one trial each, all vs. placebo. There were no differences in efficacy among biological agents and most showed statistically significant efficacy compared with placebo (nearly all exceptions were in agreement with the original study data). Serious AEs occurred very infrequently (0–8%) and an analysis was not possible. There were no differences for AEs when compared among biological agents or to placebo. Conclusion There were no statistical differences among biological agents for efficacy or safety. Overall, biological agents were effective and safe when compared to placebo. Based on these data, other considerations such as price and availability may need to be used to decide among biological agents when treating pJIA patients.

Objectives Although Familial Mediterranean fever (FMF) is categorized as autosomal recessive, frequent exceptions to this model exist and therefore we aimed to search epigenetic modifications in this disease. Methods Ten M694V homozygous FMF patients (the most severe phenotype) were recruited for this study. Patients with inflammatory flare were excluded. Total RNA was extracted from peripheral blood, and microRNA expression profiled using NanoString nCounter technology. These patients were compared to 10 healthy age- and sex-matched controls. Results Seven hundred nighty-eight mature human miRNAs were probed, 103 of which had expression levels above the negative control probes. Seven miRNAs showed significant differences in expression in samples from FMF patients compared to healthy controls: four miRNAs were upregulated (miR-144-3p, miR-21-5p, miR-4454, and miR-451a), and three were downregulated (miR-107, let-7d-5p, and miR-148b-3p). Conclusion In this pilot study, we identified epigenetic modifications in clinically quiescent FMF patients. More studies are required for exploration of their contribution to FMF pathogenesis and their potential role as clinical biomarkers.

In recent years, it has become apparent that the removal of apoptotic cells by macrophages and DC is not only noninflammatory, but also immune-inhibitory, in most although not all circumstances. Complement may be involved in the uptake of apoptotic cells via direct binding of bridging factors in some physiological circumstances, by opsonization and engagement of the complement receptors. In the current study, we use a complement-dependent system of apoptotic cell clearance by human-derived macrophages and DC. Using a luciferase reporter gene and measuring immune response to non-opsonic zymosan, we show that iC3b-apoptotic cells induce NF-kappaB inhibition in response to zymosan and LPS at the nuclear translocation, transcriptional and post-transcriptional levels, leading to profound inhibition of proinflammatory cytokines. In addition, interaction with iC3b-opsonized apoptotic cells is characterized by macrophage secretion of IL-10 and lack of TGF-beta secretion. In conclusion, in cells with iC3b receptors, opsonized apoptotic cells mediate a distinct anti-inflammatory response and transcriptional NF-kappaB-dependent blockage.

In systemic lupus erythematosus (SLE), the impairment in apoptosis can facilitate the initiation and maintenance of autoimmune responses to self antigens. Here we show that the adipocytokine leptin, which is abnormally elevated in SLE, promotes the survival and proliferation of autoreactive T-cells in mice with an autoreactive T-cell repertoire, including (NZB x NZW)F1 lupus-prone mice. This ability of leptin to promote lupus T-cell autoimmunity suggests the possibility of a therapeutic targeting of leptin in SLE.

Objective To define the optimal biologic agent for systemic JIA (sJIA) based on safety and efficacy data from a randomized controlled trial (RCT). Methods Through a systematic literature search, sJIA RCTs evaluating biologic agents were identified. The primary efficacy outcome was defined as a 30% improvement according to the modified American College of Rheumatology Paediatric 30 response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. The quality of evidence between biologic agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Results From the 493 citations originally identified, 5 RCTs were eligible for inclusion-one each for anakinra, canakinumab and tocilizumab and two for rilonacept: all vs placebo. While all were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab [odds ratio (OR) 0.10 (95% CI 0.02, 0.38), P = 0.001] or tocilizumab [OR 0.12 (95% CI 0.03, 0.44), P = 0.001]. Risks of SAEs were similar among the biologic agents (supported by very low-quality evidence) and not different from placebo. Conclusion Despite heterogeneous eligibility criteria and study designs across the five studies and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Biologic agents in sJIA seem safe and comparable with respect to SAE risk in the short term.

Henoch-Schonlein purpura (HSP) is a common, benign vasculitis in childhood which occasionally follows a protracted course and prolonged length of hospital stay. We aimed to determine clinical and laboratory characteristics that allow prediction of prolonged length of hospital stay (4 or more days) in HSP patients. We have retrospectively reviewed all HSP cases that were admitted to the Dana Duek Children's hospital between 2000 and 2013. Univariable analysis was performed to study the variables that were statistically related to length of hospital stay. These variables along with other clinically relevant variables were analyzed using stepwise backward multiple regression analysis. Variables that remained significant in the final analysis were correlated with length of stay, were each given specific weight (according to their contribution to the final R(2)) and were used to assemble an HSP presentation severity score. Out of 107 charts that were screened, 89 children were retrieved for analysis. In univariate analysis, variables that were associated with prolonged (>4 days) length of stay were: abdominal pain as initial sole presentation, C-reactive protein (CRP) 45 mg/dL (1 or 0 point) and patient's age > 6 years (0.5 or 0 points). A score of ≥3 in patients diagnosed with HSP predicted a prolonged length of stay with a positive predictive value of 93 %. The HSP presentation severity score index that we describe here may serve as a practical tool to assess severity of HSP which may eventually reflected as prolonged length of hospital stay. This score should be validated in the future in an ongoing prospective study.

Background Recurrent episodes of acute rheumatic fever (RF) may contribute to the development or worsening of rheumatic heart disease (RHD) and was estimated to occur in 50–70% of RF patients prior to the introduction of penicillin. Meta-analyses from the United States showed that secondary penicillin prophylaxis (SPP) may reduce the incidence of RHD. Moreover, SPP using monthly Intra muscular (IM) Benzathine Penicillin was more effective in prevention of RF recurrences than daily oral SPP. Objectives We aimed to evaluate the long-term adherence to SPP in RF patients using real-life data. Methods The study population included children up to 18 years old in Maccabi Healthcare Services (MHS), a 2-million member health organization in Israel, who were diagnosed with acute RF between 1/1996 to 5/2015 and were dispensed at least one monthly pack of penicillin (either in oral or IM form). Treatment persistence was defined as continuation of drug use for the entire duration of therapy or until age 18, whichever occurred first. Adherence to treatment refers to the extent of drug use during the period of persistence, expressed as mean proportion of days covered (PDC). This was calculated by dividing the quantity of penicillin dispensed by the total time span between index date and age 18, leaving MHS, or 31 April 2015, whichever occurred first. Results A total of 842 RF patients were identified. Mean (SD) ages at diagnosis among patients on oral (n=734) and IM (n=108) initial therapy were 8.6y (3.7y) and 10.9y (3.2y), respectively. The median PDC for the treatment regimens were oral: 8% [interquartile range (IQR) 2–33%] and IM: 10% (IQR 3–28%). Overall, days covered with SPP (figure 1) decreased exponentially from 103 days in the first year of therapy to 20 days in the 10th year. Conclusions Adherence and persistence to secondary penicillin prophylaxis among Israeli children diagnosed with RF is poor. Although less effective, oral SPP was the preferred regimen. Intervention plans to increase adherence and persistence to SPP must be implemented in countries where RF still exists. Disclosure of Interest None declared

Purpose Systemic lupus erythematosus (SLE) is an autoimmune disease with higher incidence and increased disease severity, including increased medication requirements and morbidity, in people not uniquely of European descent. Few studies explore the differences between ethnic groups at presentation and early in the disease process, and no studies exist to our knowledge specifically evaluating the pediatric Hispanic population. We hypothesize, based on clinical experience, that pediatric SLE patients of Hispanic descent have an earlier, more severe disease course compared to patients of European descent.

Since their recent discovery, the small noncoding RNA known as microRNAs (miRNA) have been reported to play a major role in the physiological control of gene expression and in the pathogenesis of malignant, infectious, and autoimmune disorders. In systemic lupus erythematosus (SLE), an autoimmune disease characterized by the presence of autoantibodies to multiple antigens, the role of miRNA as post-transcriptional regulators of different aspects of the disease process has recently emerged. This article reviews the pertinent literature and mechanisms of action of miRNA that have so far been associated with the pathogenesis of SLE.

Overuse of broad-spectrum antimicrobials has resulted in bacterial resistance and increasing use of relatively expensive antibiotics for community-acquired pneumonia (CAP). We hypothesized that CAP requiring parenteral medication is still curable with narrow-spectrum and inexpensive penicillin G. A prospective, randomized study was performed on 58 children aged 3 months to 15 years with CAP. Children were randomly assigned to receive low-dose penicillin G, high penicillin G, or cefuroxime intravenously for 4-7 days. The course of illness was monitored clinically and with predetermined laboratory and radiological indices for 30 days. The children recovered at the same rate with no significant differences in time to defervescence or duration of hospitalization. Observed differences in leukocyte counts and C-reactive protein at discharge were of questionable clinical significance. Penicillin G is as effective and safe as cefuroxime for CAP in otherwise healthy children, even in moderate doses.

Background The diagnostic accuracy of the classic symptoms and signs of meningitis in infants and children has not been established. Methods All children aged 2 months to 16 years with clinically suspected meningitis were eligible for this prospective cohort study at 2 large medical centers between February 2006 and October 2007. Exclusion criteria were severe chronic disease, severe immune deficiency, or idiopathic intracranial hypertension. The emergency department physician obtained information on clinical symptoms and signs and cerebrospinal fluid analysis. Meningitis was defined as white blood cell count of 6 or higher per microliter of cerebrospinal fluid. Results A total of 108 patients with suspected meningitis were enrolled. Meningitis was diagnosed in 58 patients (53.7%; 6 bacterial and 52 aseptic). Sensitivity and specificity were 76% and 53% for headache (among the verbal patients) and 71% and 62% for vomiting, respectively. Photophobia was highly specific (88%) but had low sensitivity (28%). Clinical examination revealed nuchal rigidity (in patients without open fontanel) in 32 (65%) of the patients with meningitis and in 10 (33%) of the patients without meningitis. Brudzinski and Kernig signs were present in 51% and 27% of the patients with meningitis, respectively, and had relatively high positive predictive values (81% and 77%, respectively). Bulging fontanel in patients with open fontanel was present in 50% of the patients with meningitis but had a positive predictive value of only 38%. Conclusions Classic clinical diagnostic signs have limited value in establishing the diagnosis of meningitis in children and should not be the sole determinants for referral to further diagnostic testing and lumbar puncture.

Objective: The pathological picture in ischemic tissue injury shares features with the inflammatory response. Hypoxia-mediated induction of interleukin-6 (IL-6) could set in motion the mechanisms limiting inflammation in ischemia. Intrauterine growth restriction (IUGR) represents a human model of chronic fetal hypoxia. The purpose of this study was a first-time exploration to determine whether cord blood obtained at the delivery of small-for-gestational-age (SGA) infants has increased concentrations of inflammatory markers. Study Design: Cord blood was collected from 20 SGA (term and nearterm) infants and 20 appropriate-for-gestational-age (AGA) controls. Infants exposed to maternal smoking, diabetes, maternal chronic diseases, or alcohol or drug use were excluded. Both groups had Apgar score X7 at 1min with a normal cord pH (>7.25). Cord-serum cytokines and thrombopoietin (TPO) levels were measured by enzyme linked immunosorbent assay. C-reactive protein (CRP) was measured using a turbidometric immunoassay. Result: SGA infants had a significantly smaller birth weight than AGA controls, with a smaller gestation age by 1 week. There were significant elevations in IL-6, tumor necrosis factor (TNF-a), CRP and TPO in the SGA compared with the AGA group, which persisted in multiple regression analysis even after gestational age was taken into account. Conclusion: As hypothesized, significant increases in the cord blood concentrations of known inflammatory markers were found in SGA infants compared with the controls.

Prohepcidin (Pro-Hep), synthesized in the liver, is the prohormone of hepcidin (Hep), which reduces iron absorption in the gut; its synthesis is enhanced by inflammation and is reduced during hypoxia. We aimed to study the hypothesis that infants born small for gestational age (SGA) have reduced cord blood concentrations of Pro-Hep.Cord blood was collected from 20 SGA (term and near term35 week gestation) infants and 20 appropriate for gestational age (AGA) controls. We excluded infants exposed to maternal chronic diseases, smoking, diabetes, alcohol or drug use. Both groups had a 1 min Apgar score above or equal to 7 and had normal cord blood pH (above 7.25). ELISA was used to determine serum concentrations of Pro-Hep and erythropoietin (EPO). Circulating CD71(+)/CD45(-)/SSC(low) cells were measured by flow cytometry as an index of erythroid progenitors.There were no significant differences between groups in terms of hemoglobin concentrations, and Pro-Hep. In contrast, EPO levels and circulating CD71(+)/CD45(-)/SSC(low) erythroid progenitors were significantly higher in the SGA group. These differences remained significant even after controlling for gestational age and gravidity.Contrary to EPO upregulation during intrauterine growth restriction (IUGR), and higher concentrations of circulating erythroid progenitors, Pro-Hep concentration is not affected by IUGR.

Background Systemic juvenile idiopathic arthritis (sJIA) is a severe categori of JIA, which includes systemic features such as fever, rash, elevated inflammatory markers along with poly-arthritis. It is frequently resistant to treatment. Until recently, patients were treated mainly with large doses of glucocorticoids. Breakthroughs in understanding the pathogenesis of sJIA have led to the evaluation of biologics, which block the pro-inflammatory cytokines interleukin (IL)-1 or IL-6 and their receptors. Objectives To define the optimal biological agent for sJIA based on safety and efficacy data from randomised controlled trial (RCT). Methods Through a systematic literature search, sJIA RCTs evaluating biological agents were identified. The primary efficacy outcome was defined as 30% improvement according to modified JIA American College of Rheumatology response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. Quality of evidence between biological agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Results From the 493 citations original identified, 5 RCTs were eligible for inclusion – one for each of anakinra, canakinumab, and tocilizumab, and two for rilonacept: all vs. placebo. The canakinumab trial distinguished itself from the other trials, as it included patients having high systemic involvement and low joint involvement. Conversely, the tocilizumab trial included patients with more joint involvement compared with most other trials. While all evaluated biological agents were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab (modified JIA ACR30: odds ratio 0.10 [95%CI 0.02 to 0.38], P =0.001) or tocilizumab (0.12 [0.03 to 0.44], P =0.001). Risks of SAEs were similar among the biological agents (supported by very low-quality evidence) and not different from placebo. Conclusions Despite heterogeneous eligibility criteria and study designs across the 5 studies, and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Our study also indicated that canakinumab should be considered mainly in patients with high systemic involvement and limited joint involvement, which to some extent also might be true for anakinra, whereas tocilizumab seems to be appropriate in patients with extensive joint involvement. Biological agents in sJIA seem safe and comparable with respect to SAE risk in the short term. We recognize that further data will be needed before these conclusions can be interpreted with high confidence. Protocol registration PROSPERO CRD42013004736 Acknowledgements We wish to thank The Oak Foundation for supporting the Musculoskeletal Statistics Unit, Parker Institute with unrestricted research grants. Disclosure of Interest S. Tarp Grant/research support from: paid to institute: AbbVie, Bristol-Myers Squibb, Mundipharma, and Roche, Speakers bureau: paid to institute: AstraZeneca, Pfizer, and Norpharma, G. Amarilyo Grant/research support from: Novartis, Consultant for: Novartis, I. Foeldvari Consultant for: Abbott, and Chugai, Speakers bureau: Pifzer, R. Christensen Grant/research support from: paid to institute: Abbott, Axellus, Bayer HealthCare Pharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Cambridge Weight Plan, Ipsen, Laboratoires Expanscience, MSD, Mundipharma, Norpharma, Pfizer, Roche, and Wyeth, Consultant for: paid to institute: Abbott, Axellus A/S, Bristol-Myers Squibb, Cambridge Weight Plan, Norpharma, Pfizer, Roche, Mundipharma, and Roche, J. Woo: None declared, N. Cohen: None declared, T. Pope: None declared, D. Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Consultant for: AbbVie, Actelion, Amgen, BMS, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Speakers bureau: AbbVie, Actelion, and UCB

In systemic lupus erythematosus (SLE), the availability of self-antigen promotes and fuels self-reactive immune responses. Apoptotic cells represent a major source of self-antigens, and an impairment of the removal of apoptotic material containing self-antigen can contribute to the development of autoimmunity. To address whether the adipocytokine leptin--which favors autoimmune responses through little understood mechanisms--could modulate the handling of apoptotic cells in SLE, we evaluated the ability of leptin to modulate the capacity of macrophages to phagocytose apoptotic bodies in (NZB × NZW)F1 lupus mice. It was found that leptin promoted phagocytosis of apoptotic cells by macrophages by modulating cAMP levels in macrophages. This finding associated with an increased availability of antigen that favored the development of T cell responses to apoptotic-derived antigen. As leptin promotes macrophage phagocytosis of apoptotic bodies in SLE and subsequent availability of apoptotic-derived antigen to T cells, an inhibition of this process via leptin blockade might have a therapeutic potential in SLE.

Background/Purpose: Henoch Schonlein purpura (HSP) is a common, usually benign, arthritis in childhood. However, at times, it follows a protracted course involving prolonged length of hospital stay (LOS). Objective: To determine clinical and laboratory characteristics that allow prediction of prolonged LOS in children with HSP. Methods: We retrospectively collected all consecutive cases of HSP that were admitted to the Dana-Duek Children's hospital between Jan. 1, 2000 and Sep. 30, 2013. All charts were thoroughly reviewed for demographic characteristics (e.g. age, gender), LOS (in days by date), presenting and later symptoms (abdominal pain, vomiting, GI bleeding, palpable purpura, arthralgia or periarthritis, fever) and laboratory data on admission and discharge (CBC, CRP, ESR, serum creatinine, urinalysis). In univariate analysis we studied the variables that were statistically related to LOS. Variables that significantly predicted LOS in univariate analysis or that were clinically relevant (i.e. Proteinuria (defined as positive protein in urinalysis in 2 consecutive tests), systemic fever (defined as rectal temperature ≥38.0°C), gastrointestinal (GI) bleeding, arthralgia, CRP concentration, age (years) and abdominal pain as sole presenting symptom on admission) were analyzed in stepwise backward multiple regression analysis. Variables that remained significant in the final analysis were correlated with LOS, were each given specific weight (according to their contribution to the final R square) and were used to assemble an HSP severity score. Discriminate analysis was used to determine the score best discriminating patients with prolonged LOS (4 or more days) from the others. Results: Eighty nine children (aged 9 months–17 years) were retrieved for analysis. In univariate analysis, variables that were associated with prolonged LOS were: abdominal pain as initial sole presentation (P < 0.001), CRP (P = 0.001) and systemic fever (P = 0.018). Four variables remained significant in the final stepwise multiple regression analysis, and were used as parameters in assembling the HSP severity score. The HSP severity score consisted of sole abdominal pain at presentation (0 or 3 points), Fever (0 or 2 points), CRP ≥45 (0 or 1 point) and Age ≥6 (0 or 0.5 points). A score of ≥3 predicted a prolonged LOS (4 or more days) with a sensitivity of 76%, a specificity of 79% and a positive predictive value of 93%. Conclusion: Four selected variables available on the day of admission allow predicting the severity (in terms of LOS) of HSP. This score will be validated in an ongoing prospective study.

Thirty-one consecutive infants

Background As part of the review process of new drug applications in the USA, the Food and Drug Administration (FDA) performs an independent analysis after receiving raw data from clinical trials conducted by the sponsor. From this FDA review, a critical report is available to third parties, describing the FDA analysis and conclusions. Despite the availability of these critical data, the medical community derives much of its information from journal published papers. Objectives To ascertain if there are differences between the FDA analysis and those data which are published, we undertook a direct comparison between FDA and published results of Biologics Agents (BAs) in RA, using ACR20 responses as the target outcome (often used in drug development). Methods We obtained reviews of the approved BAs for RA available on the FDA Web site, and subsequently identified phase 2 and 3 trials. We then identified matching publications in scientific journals. From both sources we extracted ACR20s and calculated odds ratios (ORs) for all active trial arms vs. controls. To compare the ORs from the FDA review and the corresponding published paper, the Ratio of ORs (ROR) were calculated for all pair-wise comparisons when ACR20 was reported in both sources. The ROR was calculated as Exp {ln(OR[FDA]) - ln(OR[Pub])}. The anticipated correlation between the two lnORs measures was estimated empirically across all the pair-wise comparisons to estimate the corresponding variance of ROR. Results RA trials were reported on 7 BAs with a total of 30 trials (2-6 trials in each FDA review) on the FDA Web site. All except one trial were published. Five trials were excluded from the analysis: in 2 trials ACR20 was reported in neither the FDA nor published paper; in 2 published papers, no ACR20 was shown and in 1 trial the FDA described no ACR20s. Out of these five, only the unpublished trial had ACR20 as the primary outcome. ACR20 was reported in 25 trials in both sources: in 21 trials the ACR20 was the primary outcome, 3 had other primary efficacy outcomes, and in 1, safety was the primary outcome. From the 25 trials, a total of 55 pair-wise comparisons were evaluated: 19 (34.6%) were in disagreement (9 were statistically significantly different, p Conclusions Discrepancies between results in published scientific journals and the FDA reviews occurred in one third of the submitted trials and comparisons. These differences can be attributed to multiple reasons. While real discrepancies occurred, there was no empirical evidence to suggest biased estimates between the FDA and published results. Increased transparency in publications would increase the credibility of published results. Acknowledgements This study was supported by a grant from Danish Medicines Agency and unrestricted grants from The Oak Foundation. *G. Amarilyo & S. Tarp contributed equally to this work. Disclosure of Interest None Declared

Purpose Paper clinical notes (PCN) have been an enduring tool in clinical medicine, but are slowly being replaced by electronic medical records (EMR) in a nationwide effort to improve clinic efficiency, to enhance interdepartmental communication, and to minimize medical errors. Our healthcare center utilizes a transitional EMR that requires outpatient clinic physicians to document patient visits on PCN and to submit them to an external department for upload to the center-wide EMR. This process generates a lag period, ranging from 1 day to 3 weeks, during which PCN are inaccessible electronically. If notes are unavailable via EMR at subsequent visits, physicians are forced to search through paper charts, which may be located in clinic or at a satellite office, thus impeding clinic workflow and lengthening patient wait time. In response, we designed, created, and implemented an EMR interface or electronic note (EMRI) that mimics the prior paper template. Physicians use a portable laptop computer in the exam room and directly upload their findings to the patient’s center-wide EMR, reducing the time required for follow-up charting. We are evaluating the workflow of the pediatric rheumatology outpatient clinics and assessing patient perceptions as we transition from PCN to a complete EMR system.