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ObjectiveCharacterization of the stages that patients with juvenile idiopathic arthritis (JIA) pass until they are diagnosed, and analysis of the different causes that lead to a delay in JIA diagnosis in Israel.MethodsThis is a retrospective cohort study conducted in 8 pediatric rheumatology centers in Israel. All patients diagnosed with JIA between October 2017 and October 2019 were included in the study. Demographic, clinical, and data regarding the referring physicians were collected from hospital and community medical charts.ResultsOf 207 patients included in the study, 201 cases were analyzed, 71.1% of the population were female. Patients, on average, were evaluated during the diagnostic process by 3.1 different physicians. In most cases, they initially met with a pediatrician in the community setting (61.2%), and later, most commonly referred to a rheumatologist by the community pediatrician (27.9%). The median time until diagnosis was 56.0 days (range: 1.0-2451.0 days). Patients diagnosed with polyarticular and spondyloarthritis/enthesitis-related arthritis (SpA/ERA) JIA subtypes had the longest period until diagnosis (median: 115.5 and 112.0 days, respectively). Younger age correlated with a quicker diagnosis, and females were diagnosed earlier compared to males. Fever at presentation significantly shortened the time to diagnosis (P< 0.01), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time (P< 0.05).ConclusionThis is the first nationwide multicenter study that analyzes obstacles in the diagnosis of JIA in Israel. Raising awareness about JIA, especially for patients with SpA/ERA, is crucial in order to avoid delays in diagnosis and treatment.

Cryopyrin-associated periodic syndromes (CAPS) also known as NLRP3-associated auto-inflammatory diseases, are a spectrum of rare auto-inflammatory diseases caused by gain-of-function mutations in the NLRP3 gene, resulting in inflammasome hyper-activation and dysregulated release of Interleukin-1β(IL-1β). Many patients with CAPS develop progressive sensorineural hearing loss (SNHL) due to cochlear auto-inflammation which, in rare cases, may be the sole manifestation. This study was undertaken to establish the suspected diagnosis of CAPS in a family presenting autosomal dominant progressive/acute SNHL and a novel missense variant in the NLRP3 gene of unknown significance (NM_001079821:c.1790G>A, p.Ser597Asn). To do so, we conducted an ex vivo functional assessment of the NLRP3 inflammasome in carries (n=10) and healthy family members (n=5). The assay revealed hyper-activation of the inflammasome among carriers, supporting the hypothesis that this missense variant is a pathogenic gain-of-function mutation. Administration of anti-IL-1 therapy resulted in a substantial clinical improvement among pediatric patients, who exhibited near resolution of hearing impairment within 1-3 months of treatment. Our findings highlight the crucial role of early diagnosis and treatment of hearing loss due to hyperactivation of the inflammasome with an anti-IL-1 agent in reversing cochlear damage. Furthermore, our results suggest that high and ultrahigh frequency ranges need to be included in the auditory assessment to enable early detection of subclinical SNHL. Finally, incorporating functional inflammasome assessment as part of the clinical evaluation could establish the diagnosis in inconclusive cases.

Objectives To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support. Methods This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease. Results Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease. Conclusion Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.

Characterization of the stages that patients with JIA pass until diagnosis, and analysis of the different causes that lead to a delay in JIA diagnosis in Israel.The study is a retrospective, cohort study that was done in eight pediatric rheumatology centers in Israel. All patients diagnosed with JIA between October 2017 and October 2019 were included in the study. Demographic, clinical, and data regarding the referral's physicians were collected from hospital and community medical charts.Of 207 patients included in the study, 201 cases were analyzed, 71.1% of the population were female. Patients on average, were evaluated during the diagnostic process by three (3.1) different physicians. In most cases, they initially met with a pediatrician in the community setting (61.2%), and later, most commonly referred to a rheumatologist by the community pediatrician (27.8%). The median time until diagnosis was 56.0 days (range: 1.0-2451.0 days). Patients diagnosed with polyarticular and enthesitis related-/spondyloarthritic (ERA/SPA) JIA subtypes had the longest period until diagnosis (median: 115.5 and 112.0 days, respectively). Younger age correlated with a quicker diagnosis, and females were diagnosed earlier compared to males. Fever at presentation significantly shortened the time to diagnosis (P0.01), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time (P0.05).This is the first nationwide multicenter study that analyzes obstacles in the diagnosis of JIA in Israel. Raising awareness of JIA, especially for patients with ERA/SPA, is crucial in order to avoid delays in diagnosis and treatment.

Approximately 40% of patients with highly elevated C-reactive protein had a normal white blood cell count. The majority of them had a bacterial infection.

Objective The representation of women among authors of peer reviewed scientific papers is gradually increasing. The aims of this study were to examine the trend of the proportion of women among authors in the field of rheumatology during the last two decades. Methods Articles published in journals ranked in the top quartile of the field of rheumatology in the years 2002–2019 were analysed. The authorship positions of all authors, country of the article's source and manuscript type were retrieved by specifically designed software. Results Overall, 153 856 author names were included in the final analysis. Of them, 55 608 (36.1%) were women. There was a significant rise in the percentage of women authors over time (r = 0.979, P Conclusion The proportion of women among authors of rheumatology articles has increased over the years, both in general and as a first or senior author; however, their proportion is still

To evaluate the ethnic distribution of Israeli patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA).The medical records of patients with PFAPA attending 2 pediatric tertiary medical centers in Israel from March 2014 to March 2019 were retrospectively reviewed. Patients with concomitant familial Mediterranean fever were excluded. Ethnicity was categorized as Mediterranean, non-Mediterranean, and multiethnic. Findings were compared with patients with asthma under treatment at the same medical centers during the same period.The cohort included 303 patients with PFAPA and 475 with asthma. Among the patients with PFAPA, 178 (58.7%) were of Mediterranean descent (Sephardic Jews or Israeli Arabs), 96 (33.0%) were multiethnic, and 17 (5.8%) were of non-Mediterranean descent (all Ashkenazi Jews). Patients with PFAPA had a significantly higher likelihood of being of Mediterranean descent than the patients with asthma (58.7% vs 35.8%; P .0001). The Mediterranean PFAPA subgroup had a significantly earlier disease onset than the non-Mediterranean subgroup (2.75 ± 1.7 vs 3.78 ± 1.9 years, P .04) and were younger at disease diagnosis (4.77 ± 2.3 vs 6.27 ± 2.9 years, P .04).PFAPA was significantly more common in patients of Mediterranean than non-Mediterranean descent. Further studies are needed to determine the genetic background of these findings.

We describe a case of Behçet’s disease (BD) in a young child that presented with recurrent neuroretinitis and developed retinal lesions during follow-up. A 4.5-year-old girl presented with fever of 39.5°C, erythema nodosum in her legs, bilateral knee arthritis, and perineum aphthae. On ocular examination, visual acuity was 20/25 in both eyes. Right eye examination was normal and the left eye (LE) showed mild anterior and intermediate uveitis, normal optic disc, and a macular star appearance. Laboratory workup demonstrated elevated C-reactive protein levels, a normal abdominal ultrasound, and a normal colonoscopy. The patient was diagnosed with BD. One month post initial presentation, the patient presented with visual acuity of finger counting in the LE with significant anterior uveitis, mild intermediate uveitis, and recurrent neuroretinitis. Under treatment of IV methylprednisolone, oral betamethasone, infliximab, and colchicine, a complete systemic remission was noticed, and uveitis became quiescent. On last examination, 4.5 years post first presentation, visual acuity was 20/25 in both eyes and the LE demonstrated a remnant of a juxtafoveal retinal scar. To the best of our knowledge, this is the first case of neuroretinitis presenting as a manifestation of pediatric BD. Ophthalmologists should be aware of these unique manifestations of ocular BD.

Behçet's disease (BD) is a variable vessel vasculitis which is rare in children.We aimed to compare the main characteristics of pediatric BD patients from Turkey versus Israel.Three centers from Turkey and two centers from Israel participated in this study. The BD diagnosis was before 16 years of age and based on expert opinion. Disease activity was assessed with BD current activity form (BDCAF).A total of 205 patients were included (165 from Turkey; 40 from Israel). HLA-B51 positivity (68.3% vs. 46.2%, p = 0.028), male gender (52% vs. 30%, p = 0.012), and skin involvement (55.2% vs. 22.5%, p0.001) were more frequent among patients from Turkey compared to patients from Israel. Tests of pathergy and HLA-B51 were more frequently performed in patients from Turkey than patients from Israel (93.3% vs. 32.5%, p0.001 and 97.6% vs. 65%, p0.001; respectively). For BD classification in the whole group, International Criteria for BD (ICBD) had the highest sensitivity (73.2%), followed by pediatric BD (PED-BD) (47.8%), and The International Study Group (ISG) (42%) criteria sets. The most commonly prescribed drug was colchicine in the whole group (96.6%). Significantly more patients were treated with corticosteroids (50% vs. 28.5%, p = 0.006), methotrexate (17.5% vs. 3%, p = 0.002), and nonsteroidal anti-inflammatory drugs (12.5% vs. 1.8%, p = 0.007) in Israel than in Turkey. The median BDCAF values were higher at the first visit for patients from Turkey compared to those in Israel (4 vs. 2, p0.001).This is the largest cohort of pediatric BD reported to date. The disease characteristics significantly differ among pediatric BD patients from Turkey and Israel, which may be due to different ethnicity and environmental factors.

ObjectivesTo evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study.MethodsPatients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg.ResultsOf the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported.ConclusioncrFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.

IntroductionPeriodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) is the most common periodic fever syndrome in the pediatric population, yet its pathogenesis is unknown. PFAPA was believed to be sporadic but family clustering has been widely observed.ObjectiveTo identify demographic and clinical differences between patients with PFAPA and a positive family history (FH+) as compared to those with no family history (FH−).MethodsIn a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31 (14.3%) had FH+. Data from patients with FH+ were compared to data from those with FH−. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demographic and clinical details.ResultsThe FH+ group as compared to the FH− group had more myalgia (56 vs. 19%, respectively, p = 0.001), headaches (32 vs. 2%, respectively, p = 0.016), and a higher carrier frequency of M694V mutation (54% vs. 25%, respectively, p = 0.05). Colchicine was seen to be a more beneficial treatment for the FH+ group as compared to the FH− group; however, with no statistical significance (p = 0.096). FMs displayed almost identical characteristics to patients in the FH+ group except for greater arthralgia during flares (64 vs. 23%, respectively, p = 0.008), and compared to the FH− group they had more oral aphthae (68 vs. 43%, respectively, p = 0.002), myalgia/arthralgia (64 vs. 19%/16%, respectively, p < 0.0001), and higher rates of FH of Familial Mediterranean fever (FMF) (45 vs.15%, respectively, p = 0.003).ConclusionsOur findings suggest that patients with a FH+ likely experience a different subset of disease with higher frequency of family history of FMF, arthralgia, myalgia, and might have a better response to colchicine compared to FH−. Colchicine prophylaxis for PFAPA should be considered in FH+.

Objective: Colchicine has been found to be highly effective for the treatment of familial Mediterranean fever (FMF). However, it is FDA-approved only for children older than 4 years owing to the lack of studies in younger children. Our tertiary pediatric rheumatology department routinely uses colchicine even in very young children with FMF. The aim of the study was to evaluate its safety and efficacy in children with FMF Methods: The departmental database was searched for all children diagnosed with FMF between 2010–2018. Those who started treatment with colchicine before age 4 years were identified and matched by MEFV variant to children who started treatment at age 4–8 years. Drug efficacy was assessed by the improvement in the frequency and duration of attacks. Adverse events were assessed according to the Rheumatology Common Toxicity Criteria ver. 2.0. Results: The cohort included 89 patients with FMF: 41 first treated before age 4 years, and 48 first treated at age 4–8 years. Rates of complete response to colchicine were 61% in the younger group and 60.4% in the older group, Corresponding rates of partial remission were 24.4% and 29.2% (p = 0.77). The most frequent adverse event was diarrhea, with a prevalence of 24.4% in the younger group and22. 9% in the older group respectively (p = 0.87). There were no significant between-group differences in other adverse events. Conclusion: Colchicine is equally effective and safe for use in patients with FMF under 4 years old, with no difference in response from older pediatric patients.

Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1 and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency (CMMRD) syndrome. In addition to a very high tumour risk, the CMMRD phenotype is often characterised by the presence of signs reminiscent of neurofibromatosis type 1. Although paediatric systemic lupus erythematosus (pSLE) has been reported so far in three patients with CMMRD, it has not been considered a diagnostic feature of the syndrome. We report here two additional female patients with pSLE and CMMRD due to biallelic pathogenic variants in MSH6. Hence, there are a total of five out of approximately 200 (2.5%) currently reported patients with CMMRD that also have pSLE, suggesting pSLE should raise the suspicion of a diagnosis of CMMRD, especially if supported by additional indicative features

Background Headache is a common complaint in children at a pediatric emergency department (PED). The primary objective of this analysis is to describe the outcome of patients presenting with headache to the PED and discharged with neurology follow up. The secondary objective is to describe the diagnostic evaluation children with headache underwent in the PED and to evaluate headache characteristics which are more likely associated with serious, life-threatening conditions. Methods A retrospective chart review of children who were discharged from the PED after evaluation for headache, with a scheduled urgent neurology outpatient clinic follow up at the same institution, over a 3.5-year period. Results During the study period, we identified 300 children whose admitting diagnosis was headache and they were discharged from the PED with a scheduled follow up. None of these patients had papilledema on fundoscopy performed by an ophthalmologist during the PED visit. Following neurology outpatient clinic visit, 62 (21%) were referred to perform brain magnetic resonance imaging. None of the patients had a diagnosis of brain tumor or any anatomic abnormality that could increase intracranial pressure. Conclusions No immediate life-threatening cases presented to the follow up neurology clinic for evaluation. A scheduled urgent neurology outpatient clinic follow up in any child with headache who is discharged from the PED, offers a safety net, even when the physical examination including fundoscopy is normal.

Familial Mediterranean Fever (FMF), the most common monogenic inflammatory disease, is mainly treated by oral Colchicine. However, 5% of patients are considered non-responders and, therefore, candidates for biologic therapy. Intravenous (IV) Colchicine treatment has been shown to be effective and safe in adult patients. The objective of this study was to evaluate the safety of IV Colchicine for pediatric FMF patients in our hospital, refractory to oral Colchicine, by reviewing their medical records. Inclusion criteria were all patients with FMF who commenced treatment with IV Colchicine before the age of 18 years, and received at least 6 months of IV therapy. The patients completed questionnaires to assess the efficacy of the treatment. Between 2004 and 2017, 7 pediatric FMF patients receiving maximal oral Colchicine doses and deemed non-responders were treated with weekly IV Colchicine, including 38 cumulative patient years of follow-up data (a full blood count, renal and liver function tests). All patients were homozygous for the M694V genotype. Long-term follow-up showed normal laboratory results with no Colchicine-related hospital admissions or toxicity. Global health assessment and the number of disease-free days have significantly improved (P

Introduction: PFAPA is the most common periodic fever syndrome in the pediatric population yet pathogenesis is unknown. PFAPA was believed to be sporadic but family clustering has been widely observed.Objective: To identify demographic and clinical differences between patients with PFAPA and a positive family history (FH+) compared to those with PFAPA with no family history (FH-).Methods: In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31 (14.3%) of patients were PFAPA FH+. Data from patients with FH+ for PFAPA was compared to data from those with FH- of the disorder. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demography and clinical details. Results: FH+ group had more headaches (32% vs.2%; p= 0.016), myalgia (56% vs. 19%; p= 0.001), higher carrier frequency of M694V mutation (54% vs. 25%; p=0.053), greater family history of FMF (30% vs. 15%; p=0.096) and better outcomes with colchicine (82% vs. 52%; p=0.096) compared to those with FH-. FMs displayed almost identical characteristics to the FH+ group except for greater arthralgia during flares (64% vs. 23%; p=0.008) and compared to the FH- group, more oral aphthae (68% vs. 43%; p=0.002), myalgia/arthralgia (64% vs. 19%/16%; pConclusions: Our findings suggest that FH+ likely experience a different subset of disease with higher frequency of family history of FMF, arthralgia, myalgia and better response to colchicine compared to FH-. Colchicine prophylaxis for PFAPA should be considered in FH+.

Rheumatic fever (RF) is an autoinflammatory disease that is caused by the host response to an infection with group A β-hemolytic streptococcus. In this case report we describe a 15 years old boy with Down syndrome who had unusual presentation of acute rheumatic fever with a fulminant multisystemic which included heart failure secondary to pancarditis and adult respiratory distress syndrome. The final diagnosis was confirmed after cardiac biopsy that was performed during valve replacement surgery and demonstrated Aschoff bodies - a pathognomonic finding in acute rheumatic fever.

Systemic sclerosis sine scleroderma (ssSSc) is a rare variant of systemic sclerosis, with only one pediatric case reported in the medical literature to date. Pulmonary arterial hypertension as the presenting feature of ssSSc is extremely rare, even in adults, and so far has never been reported in children. We report, for the first time, a case of pediatric ssSSc in a 3-year-old girl, who presented with interstitial lung disease and pulmonary hypertension. The patient was prescribed early aggressive pulmonary vasodilators combined with anti-inflammatory medications. The clinical response was good, and her current condition at 12 years of age is remarkable, considering the high mortality rates reported in adults. We underscore the importance of early aggressive treatment in future cases of similar presentation.

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 p 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.

Purpose: To report the epidemiology, etiology, ocular characteristics, treatment and visual outcome of pediatric uveitis in Israel.Methods: Retrospective study from two tertiary uveitis centers.Res...

A comparison of 23 children with inflammatory bowel disease presenting with musculoskeletal symptoms and 46 children with arthritis of other causes yielded significantly higher rates in the inflammatory bowel disease group of sacroiliitis, arthralgia, additive and recurrent arthritis, microcytic anemia, elevated inflammatory markers, and hypoalbuminemia. Clinical awareness of these findings could expedite diagnosis and treatment.

Background:The fact that mental state may serve as a trigger for attacks of periodic fever diseases is known in Familial Mediterranean fever (FMF). There is a lack of information regarding the role of emotional triggers for PFAPA attacks.Objectives:To examine whether emotional distress may trigger PFAPA attacks.Methods:Enrolled were patients with active PFAPA, from two Israeli medical centers. Researchers contacted their parents by phone in two occasions: a. within the two weeks of returning to school after the first COCID-19 lockdown; b. during the summer vacation (i.e., non-stressful period). Parents were asked regarding the occurrence of PFAPA attacks within the two weeks preceding the calls. The relative stress levels of the two periods were validated by an emotional distress scale questionnaire. Differences between occurrences of attacks during these two periods of time were recorded.Results:One-hundred and six pediatric patients enrolled in the study. Mean age was 7.37± 2.9. In the stressful period, 41 (38.7%) reported at least one attack during the preceding 2 weeks, compared to 24 (22.6%) in the non-stressful period (p = 0.017). Scores for the mean emotional distress questionnaire were higher in the stressful period compared to the non-stressful period (35.6± 8.1 vs. 32.1± 7.7, respectively, P = 0.047).Conclusion:This study shows that during a period of stress for children there were more PFAPA attacks compared to a relaxed period. These findings indicate that mental factors such as stress or excitement may be triggers for PFAPA attacks.Table 1.Attacks status during prior 2 weeks during stressful or non-stressful eventOutcomeFirst call(May 2020)Second call (August 2020)P-valuePediatric emotional distress score (PEDS), mean (±SD)35.6 (±8.1)32.1 (±7.7)0.047Any attacks during last 2 week, n (%)41 (39.8%)24 (24.2%)0.017Number of attacks0.04 One, n (%)27 (25.5%)19 (17.9%) Two, n (%)14 (13.2%)5 (4.7%)References:[1]Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43-46. doi:10.1016/S0022-3476(87)80285-8[2]Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr Int J Paediatr. 2010;99(2):178-184. doi:10.1111/j.1651-2227.2009.01554.x[3]Hall, J, Lindorff A. Children’s Transition to School: Relationships Between Preschool Attendance, Cortisol Patterns, and Effortful Control. The Educational and Developmental Psychologist. Educ Dev Psychol. 2017;34(1):1-18[4]Stokes SJ, Saylor CF, Swenson CC, Daugherty TK. A comparison of children’s behaviors following three types of stressors. Child Psychiatry Hum Dev. 1995;26(2):113-123. doi:10.1007/BF02353235[5]Førsvoll J, Kristoffersen EK, Øymar K. The immunology of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; what can the tonsils reveal. A literature review. Int J Pediatr Otorhinolaryngol. 2020;130. doi:10.1016/j.ijporl.2019.109795[6]Gidron Y, Berkovitch M, Press J. Psychosocial correlates of incidence of attacks in children with Familial Mediterranean Fever. J Behav Med. 2003;26(2):95-104. doi:10.1023/A:1023038504481[7]Makay B, Emiroğlu N, Ünsal E. Depression and anxiety in children and adolescents with familial Mediterranean fever. Clin Rheumatol. 2010;29(4):375-379. doi:10.1007/s10067-009-1330-9[8]Kraszewska-Głomba B, Matkowska-Kocjan A, Szenborn L. The Pathogenesis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome: A Review of Current Research. Mediators Inflamm 2015;2015:563876. doi:10.1155/2015/563876Disclosure of Interests:None declared

Objective: Abstracts submitted to meetings are subject to less rigorous peer review than full-text manuscripts. This study aimed to explore the publication outcome of abstracts presented at the American Academy of Ophthalmology (AAO) annual meeting. Methods: Abstracts presented at the 2008 AAO meeting were analyzed. Each presented abstract was sought via PubMed to identify if it had been published as a full-text manuscript. The publication outcome, journal impact factor (IF), and time to publication were recorded. Results: A total of 690 abstracts were reviewed, of which 39.1% were subsequently published. They were published in journals with a median IF of 2.9 (range 0–7.2) and a median publication time of 426 days (range 0–2,133 days). A quarter were published in the journal Ophthalmology, with a shorter time to publication (median 282 vs. 534 days, p =0.003). Oral presentations were more likely to be published than poster presentations (57.8% vs. 35.9%, p

Objective.The natural history of pediatric inflammatory bowel disease (IBD) patients with joint involvement has not been clearly described. Thus, we aimed to investigate phenotypic features and clinical outcomes of this distinct association.Methods.The medical records of patients with pediatric IBD diagnosed from 2000 to 2016 were reviewed retrospectively. Main outcome measures included time to first flare, hospitalization, surgery, and biologic therapy.Results.Of 301 patients with Crohn disease (median age 14.2 yrs), 37 (12.3%) had arthritis while 44 (14.6%) had arthralgia at diagnosis. Arthritis and arthralgia were more common in women (p = 0.028). Patients with arthritis and arthralgia demonstrated lower rates of perianal disease (2.7% and 4.5% vs 16.9%, p = 0.013), whereas patients with arthritis were more likely to be treated with biologic therapy (HR 2.05, 95% CI 1.27–3.33, p = 0.009). Of 129 patients with ulcerative colitis (UC; median age 13.7 yrs), 3 (2.3%) had arthritis and 16 (12.4%) had arthralgia at diagnosis. Patients with arthralgia were treated more often with corticosteroids (p = 0.03) or immunomodulator therapies (p = 0.003) compared with those without joint involvement. The likelihood to undergo colectomy was significantly higher in patients with arthralgia (HR 2.9, 95% CI 1.1–7.4, p = 0.04). During followup (median 9.0 yrs), 13 patients developed arthritis (3.3%). Arthralgia at diagnosis was a significant predictor for the development of arthritis during followup (HR 9.0, 95% CI 2.86–28.5, p < 0.001).Conclusion.Pediatric IBD patients with arthritis have distinct phenotypic features. Arthralgia at diagnosis is a predictor for colectomy in UC and a risk factor for the development of arthritis during followup.

Objective This study describes our 5-year experience treating protracted febrile myalgia syndrome (PFMS) with pulsed doses of corticosteroids. Methods Eight patients with PFMS who received pulse corticosteroid therapy were identified from the electronic database of a tertiary pediatric medical center (2011–2016). Their clinical and laboratory data were collected. Differences in continuous variables between hospital admission and discharge were analyzed using Wilcoxon’s matched pairs test. Results There were 6 female and 2 male patients of median age 10.45 years (range 6.2–17.1) Six patients were found to be homozygous for the M694V mutation. In 4 patients, PFMS was the first-ever manifestation of familial Mediterranean fever. Pulse corticosteroid therapy was administered at a dose of 10 mg/kg for 3 days. Pain was alleviated (visual analog scale score, 0) within hours of initiation of therapy, although pain flare-ups lasting for minutes to hours were still observed during hospitalization. At discharge, all patients were prescribed continuous oral corticosteroids (1–2 mg/kg) with gradual tapering down over 6 weeks. Conclusion Pulse corticosteroid therapy is effective in alleviating PFMS pain; however, it does not completely abort a PFMS episode.

Background Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is the most common periodic fever syndrome in children. There is considerable heterogeneity in management strategies and a lack of evidence-based treatment guidelines. Consensus treatment plans (CTPs) are standardized treatment regimens that are derived based upon best available evidence and current treatment practices that are a way to enable comparative effectiveness studies to identify optimal therapy and are less costly to execute than randomized, double blind placebo controlled trials. The purpose of this project was to develop CTPs and response criteria for PFAPA. Methods The CARRA PFAPA Working Group is composed of pediatric rheumatologists, infectious disease specialists, allergists/immunologists and otolaryngologists. An extensive literature review was conducted followed by a survey to assess physician practice patterns. This was followed by virtual and in-person meetings between 2014 and 2018. Nominal group technique (NGT) was employed to develop CTPs, as well as inclusion criteria for entry into future treatment studies, and response criteria. Consensus required 80% agreement. Results The PFAPA working group developed CTPs resulting in 4 different treatment arms: 1. Antipyretic, 2. Abortive (corticosteroids), 3. Prophylaxis (colchicine or cimetidine) and 4. Surgical (tonsillectomy). Consensus was obtained among CARRA members for those defining patient characteristics who qualify for participation in the CTP PFAPA study. Conclusion The goal is for the CTPs developed by our group to lead to future comparative effectiveness studies that will generate evidence-driven therapeutic guidelines for this periodic inflammatory disease.

Background: Rheumatic Fever (RF) occurs after a pharyngeal infection caused by group A-B-hemolytic streptococci, and is often classified as a connective tissue disease. RF mostly affect children and it’s diagnosis is determined using the Jones criteria. Its principal clinical significance is causing carditis at the acute phase of the disease, and valvular impairment, leading to a significant hemodynamic disturbance, as a late sequela. Despite being a completely preventable disease, Rheumatic fever continues to be the most common cause of acquired heart disease among children in developing countries. In developed countries, a sharp decline in ARF was seen in the last decades. Objectives: To examine the number of cases of Rheumatic fever in Schneider Children’s medical center, and to find whether it has declined during the years of its existence. In addition, to characterize the patient population during that period, determine the clinical characteristics of ARF, It’s risk factors and asses the course of the disease and it’s treatment. In addition, we will address the relapse rates, with an emphasis on cardiac relapses, with a correlation to preventive treatment. Methods: A retrospective cohort study was conducted, by collecting data from medical records of patients with rheumatic fever who were admitted to the Schneider Medical Center from 1993 to 2017. A database was built based on these medical records in order to assess the incidence of rheumatic fever and rheumatic heart disease, and the relapse rates, by use of descriptive and survival analysis. Results: A 402 cases with relevant diagnostic codes were examined during the follow-up period, of which 307 patients met the inclusion criteria. During the acute phase,197of the patients (64%)presented with arthritis, 159 patients (52%) with carditis, 47 patients (15%) with chorea, 16 patients(5.2%) with erythema marginatum, and 2 patients (0.7%) with subcutaneous nodules. Carditis was found in higher rates among Jewish patients than among Arabs. 31 patients (19.5%) developed severe carditis, 21 patients (13.2%) of whom developed heart failure signs, 5 were hospitalized in intensive care, and one died. There was a decrease in incidence of rheumatic fever and rheumatic heart disease during the study period. Thirty-two patients (12% of all patients with rheumatic fever) developed a relapse of the disease and 11 of whom (4 percent of all patients) developed a cardiac relapse. Median follow-up time was 49 months, and relapse rate was 13.9% after 5 years of follow-up. 15% of the patients who received oral prophylaxis experienced relapse, compared to 9% of those who received intramuscular injection therapy. The rate of recurrence among all patients with rheumatic fever was 2.8% after 2 years of follow-up, and about 7% after 8 years of follow-up. 10(90.9%) of the 11 patients with cardiac recurrence were present with carditis during the initial disease, with 7 of them (63.6% of patients with cardiac recurrence) having isolated carditis and 3 of them had a combined involvement of arthritis and carditis (27.3% of Cardiac relapses).Only in one case (9.1% of patients with cardiac recurrence) was an isolated occurrence of arthritis in the initial presentation. It was found that chorea is more common among females. Conclusion: Despite the reduction in incidence of rheumatic fever and rheumatic heart disease during the study period, the disease remains a significant cause of general and cardiac morbidity among children despite being completely preventable, therefore, It should remain in the mind of every doctor, pediatricians in particular. Disclosure of Interests: None declared

Background Clinical observations among Israeli pediatric rheumatologists reveal that some of the clinical and demographic features of Israeli children diagnosed with Juvenile Spondyloarthritis (JSpA) are different as compared to the typical characteristics described in US studies. Objectives In this study, we compared clinical, laboratory and radiographic features to determine whether differences occur between the two populations of JSpA. Methods We performed a retrospective, cross-sectional, multicenter comparison of JSpA patients from 3 large Israeli pediatric rheumatology centers and a large US pediatric rheumatology center. Patients with a diagnosis of Juvenile Ankylosing Spondylitis (JAS) and/or Enthesitis-related Arthritis (ERA) were included. The demographic, clinical and imaging features of the subjects upon presentation were compared, including MRI of the sacroiliac joints. Inter Center Comparison (ICC) between the Israeli and US musculoskeletal radiologists was conducted. Results Overall 87 patients met the inclusion criteria (39 Israeli, 48 US). As compared to the US population, the Israeli population was less likely to be male (56% vs. 75%, p=0.11), and more likely to be older at time of diagnosis (14.3 vs. 11.9 years, p Conclusion We found important distinctions between two populations with JSpA. Israeli children were more likely to present with axial disease, less likely to demonstrate HLA B27 carrier positivity, and more likely to demonstrate sacroiliitis on MRI than US children, who more commonly presented with peripheral arthritis and enthesitis, HLA-B27 positivity and negative MRI findings. These unique findings of the Israeli JSpA population, also as compared to descriptions of JSpA patients in the medical literature, point to environmental and/or population specific factors that merit additional studies in order to unravel the differences in disease presentation between the two countries. Reference [1] Shirley M. L. Tse; Ronald M. Laxer. New advances in juvenile spondyloarthritis. Nature Reviews Rheumatology, 2012, Vol.8(5), p.269–279. Disclosure of Interests Merav Heshin-Bekenstein: None declared, Naseem Ghantous: None declared, Irit Tirosh: None declared, Yonatan Butbul: None declared, Liora Harel: None declared, Yaniv Lakovsky: None declared, Pamela Weiss Consultant for: Dr. Weiss has served as a consultant for Lilly and Novartis., Nadav Rappoport: None declared, Kimberly DeQuattro: None declared, Emily von Scheven: None declared, Lianne S. Gensler Grant/research support from: Abbvie, Amgen, UCB Pharma , Consultant for: Novartis, Lilly, Janssen, Amir Hendel: None declared, John MacKenzie: None declared, Gil Amarilyo: None declared

Background Colchicine has been found to be highly effective for the treatment of familial Mediterranean fever (FMF). However, it is FDA-approved only for children older than 4 years owing to the lack of studies in younger children. Objectives Our tertiary pediatric rheumatology department routinely uses colchicine even in very young children with FMF. The aim of the study was to evaluate its safety and efficacy in children with FMF Methods The departmental database was searched for all children diagnosed with FMF between 2010-2018. Those who started treatment with colchicine before age 4 years were identified and matched by MEFV variant to children who started treatment at age 4-8 years. Drug efficacy was assessed by the improvement in the frequency and duration of attacks. Adverse events were assessed according to the Rheumatology Common Toxicity Criteria ver. 2.0. Results The cohort included 89 patients with FMF: 41 first treated before age 4 years, and 48 first treated at age 4-8 years. Rates of complete response to colchicine were 61% in the younger group and 60.4% in the older group. Corresponding rates of partial remission were 24.4% and 29.2% (p=0.77). The most frequent adverse event was diarrhea, with a prevalence of 24.4% in the younger group and22. 9% in the older group (p=0.87). There were no significant between-group differences in other adverse events. Conclusion Colchicine is equally effective and safe for use in patients with FMF under 4 years old, with no difference in response from older pediatric patients. IQR-interquartile range Values are n(%) unless otherwise indicated. AEs – adverse events * RCTC- Rheumatology Common Toxicity Criteria, version 2.0 for AE severity:0-no, 1-- mild, 2 – moderate, 3 – severe, 4 – life-threatening Values are n (%) unless otherwise indicated. § Due to statistical limitations, Statistic analysis (Fisher’s exact test) was performed between No AEs & RCTC score 1 and RCTC score 2-4 in the respected age groups. †Data available for 34 patients. ‡Data available for 43 patients. Disclosure of Interests None declared

Background Behcet’s disease (BD) is a variable vessel vasculitis affecting all sizes of vasculature in both the arterial and venous systems. Children with BD comprises 3-24% of all BD patients. Objectives To compare the demographics, presentation, clinical manifestations, disease activity, and treatment in pediatric Behcet’s disease in Turkey versus Israel. Methods Three centers from Turkey and two centers from Israel participated in this study. The diagnosis of BD was before 16 years of age and based on expert opinion at each center. BD current activity form (BDCAF) was used for assessing disease activity. Results A total of 205 patients were included (165 from Turkey; 40 from Israel). HLA-B51 positivity (68.3% vs 46.2%, p=0.028), male gender (52.1% vs 30%, p=0.012), and skin involvement (especially necrotic folliculitis) (55.2% vs 22.5%, p Conclusion This is the largest cohort of pediatric BD reported to date. The disease manifestations and disease activity significantly differ among pediatric BD patients from Turkey and Israel which emphasizes the effect of the ethnicity on disease phenotype. Reference [1] Kone-Paut I, et al. Consensus classification criteria for paediatric Behcet’s disease from a prospective observational cohort: PEDBD. Ann Rheum Dis 2016;75:958-64. Disclosure of Interests Yonatan Butbul: None declared, Ezgi Deniz Batu: None declared, Hafize Emine Sonmez: None declared, Betul Sozeri: None declared, Nuray Aktay Ayaz: None declared, Limor Baba: None declared, Gil Amarilyo: None declared, Seval Simsek: None declared, Liora Harel: None declared, Serife Gul Karadag: None declared, Yelda Bilginer: None declared, Seza Ozen Consultant for: Seza Ozen is receiving consultancy fees from Novartis, Speakers bureau: Roche