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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.

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.

Objective To investigate phenotypic and molecular characteristics of a consanguineous family with autosomal-recessive, polyarticular, juvenile isiopathic arthriris (JIA) with extra-articular manifestations, including renal amyloidosis and Crohn’s disease, associated with a novel homozygous truncating variant in LACC1. Methods Whole exome sequencing (WES) or targeted Sanger verification were performed in 15 participants. LACC1 expression and cytokine array were analysed in patient-derived and CRISPR/Cas9-generated LACC1-knockout macrophages (Mϕ). Results A homozygous truncating variant (p.Glu348Ter) in LACC1 was identified in three affected and one asymptomatic family member, and predicted harmful by causing premature stop of the LACC1 protein sequences, and by absence from ethnically-matched controls and public variation databases. Expression studies in patient-derived macrophages (Mϕ) showed no endogenous p.Glu348Ter-LACC1 RNA transcription or protein expression, compatible with nonsense-mediated mRNA decay. WES analysis in the asymptomatic homozygous subject for p. Glu348Ter-LACC1 detected an exclusive heterozygous variant (p.Arg928Gln) in complement component C5. Further complement activity analysis suggested a protective role for the p.Arg928Gln-C5 variant as a phenotypic modifier of LACC1-associated disease. Finally, cytokine profile analysis indicated increased levels of pro-inflammatory cytokines in LACC1-disrupted as compared with wild-type Mϕ. Conclusions Our findings reinforce the role of LACC1 disruption in autosomal-recessive JIA, extend the clinical spectrum and intra-familial heterogeneity of the disease-associated phenotype, indicate a modulatory effect of complement factor C5 on phenotypic severity, and suggest an inhibitory role for wild-type LACC1 on pro-inflammatory pathways.

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.

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.

INTRODUCTION: New Eurofever/PRINTO classification criteria (EPCC) for Familial Mediterranean Fever (FMF) and other recurrent fevers have been recently developed, together with the classification of the pathogenicity of MEFV variants. OBJECTIVES: To evaluate the impact in real life of both the EPCC and INSAID pathogenicity classification of MEFV variants in the large international Eurofever FMF cohort. METHODS: Baseline demographic, genetic and clinical data of FMF patients included in the Eurofever registry were evaluated. The EPCC and the 2018 INSAID classification for MEFV variants were applied in all eligible FMF patients. RESULTS: Since November 2009, clinical information was available for 1012 FMF (532 males/480 females, 827 children/185 adults) from 119 centres. Complete data were available for 887 patients in whom 623 (70.2%) satisfied EPCC (EPCC+), while 264 (29.8%) did not (EPCC-). The majority of the EPCC- patients (172, 65.1%) displayed negative or non-informative genetics (monoallelic or biallelic benign variants, monoallelic variant of unknown significance). At baseline, colchicine was used in most of EPCC+ patients (88%) and in a lower percentage of EPCC- patients (69%, p

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+.

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+.

ObjectiveColchicine has been considered a lifelong therapy for familial Mediterranean fever (FMF). Recent studies describe patients who discontinued colchicine, but there is a lack of data pertaining to predictors of success. The aims of our study were to describe a cohort of pediatric patients with FMF who discontinued colchicine therapy, and to identify factors predicting successful termination of colchicine.MethodsThis study describes a cohort of pediatric patients with FMF who discontinued colchicine therapy following a relatively prolonged attack-free period (> 6 months), and identifies factors predicting successful termination. Data collected included demographic, clinical, and laboratory characteristics of children diagnosed with FMF aged < 16 years who underwent a trial of colchicine discontinuation. Data from patients who successfully ceased colchicine therapy were compared to those of patients who relapsed.ResultsOf 571 patients with FMF, 59 (10.3%) discontinued colchicine therapy. The average attack-free period before enrollment was 0.97 ± 1.4 years. Follow-up after ceasing colchicine was 5.0 ± 3.05 years, during which time 11 (20%) patients had an attack. The most common symptoms were fever (100%) and abdominal pain (80%). For those failing discontinuation, colchicine was restarted within 1.3 years (range 0.3–5.0, median 0.7 yrs). A longer attack-free period prior to colchicine discontinuation predicted success. Myalgia and arthritis prior to colchicine cessation were more common among children who required renewal of colchicine.ConclusionCessation of colchicine therapy should be considered following prolonged remission in a select group of patients. Patients with arthritis or myalgia are more likely to have an attack after ceasing colchicine therapy.

Background Familial Mediterranean fever (FMF) is an autosomal recessive, auto-inflammatory disease, presenting with recurrent bouts of fever and polyserositis. FMF has been associated with central nervous system (CNS) manifestations such as Headache and Myalgia. The occurrence of other forms of nervous system involvement is rare, including seizures, sinus vein thrombosis, pseudotumor cerebri and more. There are only few case reports of aseptic meningitis due to FMF. Case presentation We present the case of a 14 year-old girl diagnosed with FMF, who experienced recurrent episodes of severe headache and aseptic meningitis while on maximal dose of colchicine therapy. She had a dramatic response to anakinra with symptoms resolving completely within a few days without recurrence. Subsequently, we identified seven cases in the literature describing recurrent aseptic meningitis in patients with underlying FMF; all showed response to colchicine treatment, without treatment failure. Conclusion Our case suggests a role for Interleukin 1 (IL-1) antagonists for cases of CNS involvement secondary to FMF in patients who fail to respond to colchicine, and might imply that anakinra could be effective in other auto-inflammatory diseases with CNS involvement.

Background Behcet's disease (BD) is a multisystem autoinflammatory disease of unknown etiology. Cardiopulmonary involvement is rare, especially in young patients, and carries high morbidity and mortality rates. Aim Of 26 patients with pediatric BD enlisted in our center, we encountered three patients with severe atypical cardiorespiratory presentations. Our aim was to describe the manifestations and the course that led to the diagnosis of BD. Results Three adolescents presented with intracardiac thrombi and left anterior descending obstruction causing myocardial infarction, pulmonary artery aneurysm with pulmonary embolism in situ, and suspected epiglottitis. Two patients had a delayed diagnosis of BD, and all had a good response to anti-inflammatory agents. Conclusions This study demonstrated that pediatric BD is associated with atypical cardiopulmonary manifestations which maybe life threatening. Since diagnosis maybe challenging, a high index of suspicion is needed especially in young patients, to promptly diagnose and treat these complications. Cardiopulmonary signs and symptoms, though uncommon, maybe the first manifestation and a clue to the diagnosis of this rare disease.

Pediatric inflammatory multisystem syndromes associated with Severe Acute Respiratory Syndrome Coronavirus 2 are emerging in recent reports. We describe a patient with critical illness consistent with atypical Kawasaki disease with cardiac dysfunction and abdominal involvement presenting weeks after Severe Acute Respiratory Syndrome Coronavirus 2 infection. Our patient showed unique central nervous system involvement with small vessel vasculitis and profound hypocomplementemia, both not previously reported in case descriptions and may hint at possible disease mechanisms.

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.

Autologous hematological stem cell transplantation (HSCT) is a novel therapy for systemic sclerosis (SSc) that has been validated in three randomized controlled trials.To report the first Israeli experience with HSCT for progressive SSc and review the current literature.Five SSc patients who were evaluated in our department and were treated by HSCT were included. Medical records were evaluated retrospectively. Demographic, clinical, and laboratory data were recorded. Continuous data are presented as the mean ± standard deviation. Categorical variables are presented as frequencies and percentages.Five SSc patients were treated with HSCT. Four patients were adults (mean age 53 ± 12 years) and one was a 12-year-old pediatric patient. All patients were female. HSCT was initiated 1.4 ± 0.8 years after diagnosis. Two patients were RNA POLIII positive, two were anti-topoisomerase 1 positive, and one only antinuclear antibodies positive. All patients had skin and lung involvement. The mean modified Rodnan Skin Score was 29 ± 4.7 before HSCT, which improved to 10.4 ± 9.6 after HSCT. The forced vital capacity improved from 68 ± 13% to 90 ± 28%. Diffusing capacity of the lungs for carbon monoxide increased by 6%. Among severe adverse events were cyclophosphamide-related congestive heart failure, antithymocyte globulin-related capillary leak syndrome, and scleroderma renal crisis. All symptoms completely resolved with treatment without sequela. No treatment related mortality was recorded.HSCT is an important step in the treatment of progressive SSc in Israel. Careful patient selection reduces treatment related morbidity and mortality.

Juvenile psoriatic arthritis (JPsA), a subtype of juvenile idiopathic arthritis (JIA), constitutes 5% of JIA. The literature is inconsistent regarding features of JPsA, and physicians debate whether it is a distinct entity within JIA. A biphasic age of onset distribution has been noted. Early-onset disease is characterized by female predominance, small joint involvement, dactylitis, and positive antinuclear antibodies. Late-onset JPsA resembles adult-onset psoriatic arthritis (PsA), with male predominance, psoriasis, enthesitis, and axial disease. Recent studies report improved outcomes, likely due to the widespread use of traditional and biologic disease-modifying antirheumatic drugs. Conflicting HLA associations have been reported in JPsA, but notably both HLA class I and II allele associations are suggested. Similar to PsA cohorts, subjects with JPsA have a lower frequency of a protective interleukin 23R allele than controls or other JIA subtypes. Data in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) patient registry suggest the aggressive characteristics of JPsA: 24.6% of children have joint damage 4.6 years after symptom onset. Pediatric and adult PsA classification criteria define different JPsA cohorts within the registry and support a previous suggestion that the International League of Associations for Rheumatology criteria for JPsA may be overly stringent. Increased collaboration between pediatric and adult physicians and comparative research on these clinically related conditions are warranted.

Background Some children with autism spectrum disorder (ASD) have highly specific food selectivity and therefore are prone to nutritional deficiencies of different kinds. Patients We document three children with ASD who presented with refusal to walk and gingivitis who underwent comprehensive evaluations before establishing the diagnosis of vitamin C deficiency (scurvy). The symptoms resolved after treatment with vitamin C. Conclusions Prevention of nutritional deficiencies in children with ASD is essential, and providing multivitamin supplementation whenever high food selectivity is noted may prevent significant morbidity.

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.

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.

Atherosclerosis is emerging as one of the most important causes of morbidity and mortality among patients with different rheumatologic disease. Endothelial dysfunction may be an early sign of atherosclerosis.To evaluate the occurrence of endothelial dysfunction in children with autoimmune diseases, including juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE) and dermatomyositis, using a novel noninvasive technique.The study group consisted of 24 children with autoimmune diseases, and was compared to a control group of 17 healthy, age- and BMI-matched controls. Endothelial function was assessed by a noninvasive technology that captures a beat-to-beat plethysmographic recording of the finger arterial pulse-wave amplitude with pneumatic probes, utilizing a Peripheral Arterial Tonometry (PAT) device.In the study group, 7 out of the 24 (29%) patients had evidence of impaired endothelial function, compared to 1 out of 17 (6%) children in the control group (p0.05). Thirty-three per cent of our patients with SLE and 23% of patients with JIA had impaired endothelial function. There were no differences between the two groups of patients with and without endothelial dysfunction as to age, body mass index, fasting glucose level, triglycerides, cholesterol, and dose and duration of steroid treatment. The patients with normal endothelial function had higher systolic blood pressure compared with the group with impaired endothelial function (112.82 ± 7.65 vs13.88 ± 104.85 respectively, p=0.04).Children with autoimmune diseases may have a high tendency to develop endothelial dysfunction. Larger studies are needed to confirm our findings and to explore the influence of endothelial dysfunction on the development of atherosclerosis in young children.

Background Although Henoch-Schonlein purpura (HSP) is the most common form of systemic vasculitis in children, the long term effect of HSP on endothelial function is still not clear. The aim of our study was to evaluate the long term effect of HSP on endothelial function in children and adolescents. Methods This research was an observational prospective study. The study group comprised of 19 children diagnosed with HSP. The minimum interval between the diagnosis with HSP and endothelial testing was 5 months. Endothelial function evaluation was assessed by a noninvasive technology named peripheral arterial tonometry, using an EndoPAT™ device. This method measures blood flow in the limb, in response to arterial occlusion, and calculates a Reactive Hyperemic Index (RHI) as an index of endothelial function. RHI values of the study group were compared to those of a known control group. Results Nineteen children and adolescents with HSP underwent endothelial function studies. Endothelial function was compared to that of a known control group comprising of 23 healthy children and adolescents. The two groups had similar characteristics, including age, male to female ratio, height, weight and BMI. Mean RHI was 1.81 in the study group, and 1.87 in the control group (p = 0.18). Linear regression of the study group, showed a positive correlation between the time interval from HSP diagnosis to participation in the study, and between the RHI value (r = 0.542, p = 0.016). RHI levels were significantly higher in patients who had endothelial function measured more than 6 years since the diagnosis of HSP compared with those patients with less than 6 years follow up (1.98 + 0.74 vs. 1.38 ± 0.43 P = 0.037). Conclusions These results suggest that HSP causes short term endothelial dysfunction that improves with time.

Behçet's disease (BD) is a variable vessel vasculitis. The most widely used classification criteria for adults is the International Behçet's Study Group (ISG) criteria. Recently, the paediatric BD (PEDBD) classification criteria has been developed for children. For disease activity, there are mainly two severity scores; the Iranian BD dynamic activity measure (IBDDAM) and BD current activity form (BDCAF). We tested the performances of PEDBD and ISG criteria and the correlation between severity scores and physician global assessment (PGA) in children with BD.Thirty BD patients from Hacettepe University, Ankara, Turkey; 24 from Erciyes University, Kayseri, Turkey; and 14 BD patients from Rambam Medical Centre, Haifa, Israel were included. As controls, children with systemic lupus erythematosus, polyarteritis nodosa, and Crohn disease from Turkey and Israel were included. The sensitivity and specificity of the PEDBD and ISG criteria were evaluated based on the features of the patients before or at 16 years of age. The gold standard for the diagnosis of BD was based on expert opinion at each centre. Expert PGA (visual analogue scale between 0-10; where 0 indicates no disease activity), IBDDAM, and BDCAF were evaluated at the time of diagnosis and at last follow-up in all patients.Sixty-eight BD (disease onset≤16 years; 44.1% male) and 90 control patients were included. The sensitivity and specificity of PEDBD/ISG criteria were 73.5%/52.9% and 97.7%/100%, respectively. Thirty-two (47%) patients with BD failed to fulfill ISG criteria while almost all met PEDBD criteria. The median (interquartile range; IQR) IBDDAM and BDCAF scores at diagnosis were 6(4)/4(2); significantly decreased to 1(2)/1(2), respectively at latest follow-up (p0.001 for both). The median (IQR) PGA score at diagnosis was 5(2); significantly decreased to 1(2) at latest follow-up (p0.001). IBDDAM positively correlated with BDCAF (r=0.637; p0.001). PGA positively correlated with BDCAF and IBDDAM (r=0.502; p0.001 and r=0.624;p0.001, respectively).In our study, the PEDBD criteria showed better sensitivity than ISG criteria which is a big advantage for paediatric patients for early diagnosis. We also demonstrated that the severity scores were positively correlated with each other and PGA; thus may be used in clinical practice for paediatric BD patients.

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.

Rituximab (RTX) is a chimeric anti-CD20 antibody, approved for rheumatoid arthritis (RA) patients who failed anti-Tumor Necrosis Factor therapy. It has been used occasionally for life-threatening autoimmune diseases (AID). We report our center experience in the use of RTX in life-threatening complications or refractory AID. Clinical charts of patients treated with RTX at our center were reviewed, cases treated for life-threatening complications or refractory AID were analyzed. Acute damage to vital organs such as lung, heart, kidney, nervous system with severe functional impairment were defined as life-threatening complications; treatment failure with high-dose corticosteroids, cyclophosphamide, IVIG, plasmapheresis was defined as refractory autoimmune disease. During the years 2003-2009, 117 patients were treated with RTX, most of them for RA. Nine patients (6 females, mean age 51.5 years, mean disease duration 6.3 years) answered the criteria. The indications were as follows: pulmonary hemorrhage (1 patient with cryoglobulinemic vasculitis, 1 with systemic sclerosis, 1 with ANCA-associated vasculitis), catastrophic anti-phospholipid syndrome (2 SLE patients), non-bacterial endocarditis and pulmonary hypertension (1 patient with mixed connective tissue disease), vasculitis and feet necrosis (1 patient with systemic lupus erythematosus), severe lupus demyelinative neuropathy and acute renal failure (1 patient), and severe rheumatoid lung disease with recurrent empyema and pneumothorax (1 patient). B cell depletion was achieved in all patients. The median time since starting of complications to RTX administration was 3 weeks (range 2-15 weeks). Complete remission (suppression of the hazardous situation and return to previous stable state) was seen in 7 out of 9 patients. Partial remission (significant improvement) was achieved in the remained. The median time to response was 3 weeks (range 1-8 weeks), mean follow-up 47.2 months (range 6-60 months). A rapid tapering off of steroids was achieved in all patients. Two patients relapsed and were successfully retreated with RTX: the patient with severe RA lung relapsed after 3 years, one of the patients with ANCA-associated pulmonary alveolar hemorrhage relapsed after 10 months. There were no side effects during RTX infusion. Two episodes of serious infections were registered: fatal Gram-negative sepsis 6 months after RTX treatment, and septic discitis 4 months after receiving RTX. RTX serves as a safe, efficient, and prompt rescue therapy in certain life-threatening conditions and resistant to aggressive immunosuppression AID. RTX when administrated at an earlier stage, prevented irreversible vital organ damage, and allowed rapid steroid tapering off in already severe immunodepressed patients.

Objectives. To determine and compare the prevalence of disturbed sleep in JIA and JDM and the relationship of sleep disturbance to pain, function, disease activity and medications. Methods. One hundred fifty-five patients (115 JIA, 40 JDM) were randomly sampled and were mailed questionnaires. Sleep disturbance was assessed by the sleep self-report (SSR) and the children’s sleep habits questionnaire (CSHQ). Fatigue, pain and function were assessed by the paediatric quality of life inventory (PedsQL) and disease activity by visual analogue scales (VASs). Joint counts were self-reported. Results. Eighty-one per cent responded, of whom 44% reported disturbed sleep (CSHQ > 41); there were no differences between disease groups. Poor reported sleep (SSR) was highly correlated with PedsQL fatigue (r = 0.56, P < 0.0001). Fatigue was highly negatively correlated with quality of life (r =0.77, P < 0.0001). The worst pain intensity in the last week was correlated to sleep disturbance (r = 0.32, P = 0.0005). Fatigue was associated with prednisone and DMARD use. Conclusions. Sleep disturbance and fatigue are prevalent among children with different rheumatic diseases. Sleep disturbance and fatigue are strongly associated with increased pain and decreased quality of life. Strategies aimed at improving sleep and reducing fatigue should be studied as possible ways of improving quality of life for children with rheumatic illness.

Objective To evaluate the efficacy of colchicine in reducing the frequency of attacks in patients with PFAPA. Study design We conducted a 6-month open label, randomized, controlled study among patients with PFAPA who attend the Pediatric Rheumatology Clinic at the Rambam Medical Center in Israel. A total of 18 patients aged4 –11 years (males:females ratio=11:7) were randomized into a control group (I, 10 children) and a study group (II, 8 children). Group I was followed for 6 months without any intervention, and group II was initially followed for 3 months and was thereafter treated with colchicine for 3 additional months, according to standard regimen. During the 6-month period of the study the patients and their physician recorded all the episodes of PFAPA in a constructed log. DNA analyses for the 5 common FMF mutations in Israel were performed in 17 out of the 18 patients. Results The number of episodes during the first 3 months was similar in both groups (group I 3.2 ± 1.5, group II 4.9 ± 2.3; p ≤ 0.12). Group II had significantly less PFAPA attacks in the second period while on colchicine therapy (4.9 ± 2.3 vs. 1.6 ± 1.2; p ≤ 0.01), in opposition to group I, where no difference in the number of attacks was noted between the first and second period of follow-up (3.2 ± 1.5 vs. 2.7 ± 1.5; p = 0.33). Of the 17 patients tested, 8 were carriers for FMF mutations (2 in group I and 6 in group II). Conclusion Colchicine prophylaxis seems to be effective in reducing the number of attacks in PFAPA.

Background Following the introduction of the ILAR criteria for juvenile idiopathic arthritis, juvenile psoriatic arthritis (JPsA) has become a better recognized category within the inflammatory arthritides of childhood. There are fewer reports describing the characteristics and long-term outcome of patients with JPsA than other subtypes of JIA. The aim of our study was to determine the long-term outcome and clinical course of patients with juvenile psoriatic arthritis (JPsA) and to define subgroups of JPsA. Methods Clinical records of all patients meeting criteria for JPsA were reviewed and divided into 4 groups depending on their clinical features and onset type. Patient characteristics and clinical features at onset and during follow-up were determined. Results The cohort consisted of 119 patients: 65 with oligoarticular-onset (55%; persistent 44 and extended 21), 34 (29%) with RF(-) and 4 (3%) RF(+) polyarticular and 16 (13%) enthesitis-related arthritis (ERA). At diagnosis patients with ERA were oldest and more commonly male (p=0.001 and =0.01 respectively). Patients with a polyarticular course had more involvement of small joints of the hands and wrist when compared to patients with persistent oligoarticular and ERA (p Outcome: Time to first inactive disease on, but not off, therapy was significantly longer among patients with polyarticular course when compared to oligoarticular and ERA (p=0.016 and p=0.48 respectively). Patients with polyarticular course more frequently had contractures during follow-up than other groups (p=0.01). Conclusion The long-term outcome of with JPsA was generally good. Patients with JPsA did not appear to form distinct sub-group of patients but rather resembled JIA patients with onset types without psoriasis.

Introduction Prolidase deficiency (PD) is a rare autosomal recessive disorder which may have a wide spectrum of clinical features. These features include a characteristic facies, cognitive impairment, rashes or skin ulceration, splenomegaly, recurrent infections involving mainly the respiratory system, and iminodipeptiduria. The disorder is caused by a mutation in the PEPD gene. Objective To describe a cohort of unrelated PD patients from Northern Israel whose inborn error of metabolism was associated with systemic lupus erythematosus (SLE) and to identify in the medical literature all PD cases mimicked by and/or associated with SLE. Methods Three patients with PD associated with SLE were clinically, biochemically and genetically investigated. These patients were from 3 unrelated consanguineous families residing in Northern Israel. A computer-assisted (PubMed) search of the medical literature from 1975 to 2011 was performed using the following key words: Prolidase deficiency, SLE, and systemic lupus erythematosus. Results An association between PD and SLE was found in 10 PD patients. These 10 patients included three from our cohort of 23 PD patients, and seven out of just under 70 PD patients previously reported in the literature. Conclusion The present findings underscore the relatively high incidence of the association between SLE and PD, suggesting that this association may not be coincidental. The phenotypic similarities between SLE and PD might suggest that the PEPD gene constitutes a modifier gene or a genetic risk factor in the causation of SLE.

Plasma procalcitonin (PCT) increases rapidly during bacterial infections but remains low in viral infections and other inflammatory processes. High plasma PCT typically occurs in children with bacterial meningitis, severe bacterial infections, particularly in cases of septic shock or bacteremia, and in renal parenchymal damage. The aim of this study was to test the usefulness of plasma PCT analysis in the diagnosis of osteomyelitis, septic arthritis, and other skeletal inflammatory diseases in pediatric patients admitted because of fever and limping.White blood cell count, erythrocyte sedimentation rate, C-reactive protein, and PCT levels were measured in children admitted to the pediatric department with fever, limping, and suspected osteomyelitis or septic arthritis. PCT levels were measured by an immunochromatography assay, based on monoclonal and polyclonal antibodies against katacalcin.Forty-four children were evaluated: 12 (27.3%) were diagnosed with osteomyelitis, 11 (25%) had septic arthritis, 5 children (11.4%) were diagnosed as a soft tissue infection, and transient synovitis or reactive arthritis was diagnosed in another 6 children (13.6%). Four children (9.1%) were diagnosed as having juvenile rheumatoid arthritis, and 6 (13.6%) with different diseases. PCT value was elevated in 7 patients (58.3%) with osteomyelitis, and only 3 children (27.2%) with the diagnosis of septic arthritis had a mildly elevated value. Among the children with other diagnosis, there were no positive PCT values (P0.001 between skeletal infection and all other diagnosis).In this study, PCT was found to be a useful marker in the diagnosis of osteomyelitis and not in septic arthritis. A larger group of patients needed to be studied to confirm our findings.

Objective: Acute mastoiditis is a serious bacterial infection of the temporal bone and is the most common complication of otitis media. The goal of this study is to assess the clinical features, pathogens, management, and outcome of acute mastoiditis in children in northern Israel. Methods: A systematic review of medical records of all children who were admitted with acute mastoiditis from January 1990 through December 2000. Results: Fifty-seven children were included. Median was age: 36 months. In 26 patients (45.6%) mastoiditis complicated the first episode of acute otitis media (AOM). Twenty-five children (44%) received antibiotic treatment prior to admission. Frequent symptoms included mastoid area erythema in 54 children (94.7%), proptosis of the auricle in 52 children (91.2%) and fever in 43 children (75.4%). Middle ear, and subperiostal culture yielded growth of pathogen in 30 children (75%), two cultures yielded more then one pathogen. The most frequent pathogens were: Pseudomonas aeruginosa in 10 children (25%), Streptococcus pneumoniae in eight children (20%), Group A streptococcus in six children (15%). The highest incidence of Streptococcus pneumoniae was found in children who did not suffer from AOM before admission (35 vs. 5%). Fifty-two (91.2%) children were cured with antibiotic treatment alone. Seventeen children underwent computed tomography (CT) of the mastoid. Mastoid bone destruction was demonstrated in six children and subperiostal abscess in eight. Mastoidectomy was performed in five children. Conclusions: The diagnosis of acute mastoiditis can be made on clinical basis alone requiring CT only when complications are suspected. Half of the children admitted with acute mastoiditis had no previous history of recurrent AOM. In those children S. pneumoniae was the leading pathogen while P. aeruginosa was more prevalent in children with recurrent AOM. Most of the children recovered with medical therapy alone, without surgical intervention.

Background/Purpose: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome. FMF is caused by mutations in the MEFV gene which encodes the pyrin protein, that has an important role in the activation of IL-1β. Evidence from case reports/series and one controlled study supports IL-1 blockage as a potential treatment for FMF. Canakinumab (CAN) is a selective fully human monoclonal anti-IL-1β antibody. This study served as a proof of concept to evaluate the role of CAN in the treatment of pediatric colchicine resistant (CR)-FMF with a longterm extension. Methods: This was a 2-center, 2-part, phase II, open-label, single-arm study. Subjects consisted of CRFMF patients (pts) 4–16 years of age, with a history of ≥3 documented FMF attacks in the 3 months prior to enrollment. In part I, pts with an investigator-confirmed FMF attack during the 30-day run-in period (RI) could enter the treatment phase. These subjects received the 1st dose of CAN (2 mg/kg, max 150 mg) via subcutaneous (SC) injection during the subsequent attack and then every 4 weeks for three times. The dose was doubled to 4 mg/kg (max 300 mg) if an attack occurred between Day 1 and Day 29 visits. Primary outcome was the proportion of pts with ≥50% reduction in FMF attack rate during the treatment vs. pretreatment period. Following the end of the treatment period, pts were followed until day 144 or until an attack occurred, whichever occurred first. CAN was then renewed and pts entered the long-term extension study (part II), in which the dose and frequency of CAN administration and colchicine dose could be adjusted by investigators based on pt response. Results: Seven pts (5 males, 2 females; median age 9.5 yrs, range 6.8–14.9) received treatment. In part I, 6/7 (86%) pts attained the primary outcome. The median attack rate was reduced by 89% from 2.7 to 0.3 per 28 days; 2 pts had their CAN dose uptitrated. Elevated median baseline CRP normalized by Day 8 with ESR and SAA by Day 28. Following the end of the treatment period 5 pts developed attacks within a median of 25 days. In part II, all 7 pts (no drop-outs) were followed for a median of 17 (range 13–25) months. During this period, 3 pts experienced 6 attacks (0.05 attacks per pt month) and in 2 pts the CAN doses were increased. Two additional pts experienced 3 mild increases in the ESR and CRP (not associated with an attack) that resolved after CAN dose increase. At the end of part II, the global physician assessment was rated as very good for all pts; median CAN dose was 3 (range 1.8–4.8) mg/kg with administration interval lengthened in 3 pts to every 7 wks. Colchicine dose was decreased to 1 mg/d in 3 pts and discontinued (by self) in 1 pt. 22 AEs were recorded in 5 pts, with 11 in each study part. All were mild except for 3 moderate AEs (Strep throat infection, laceration, tinea capitis) assessed as unrelated to study treatment by the study investigators. No AEs led to medication discontinuation. Conclusion: This study demonstrated the longterm therapeutic effect of canakinumab in pediatric pts with CR-FMF. AEs were manageable. Occasional increases in dose were needed while the dosing interval could be lengthened in some patients. A larger study is needed to better evaluate the benefit and optimal dosing of canakinumab for CR-FMF.

Background/Purpose: Few reports have focused on vascular endothelial function in children with Henoch-Schonlein purpura (HSP). The purpose of the present study was to assess the long term effect of HSP on endothelial function, in children and adolescents. Methods: Patients between 6–20 years old, who were diagnosed as having HSP according to ACR Criteria, were included in the study. All patients were followed by the rheumatologic clinic at Meyer children's hospital Israel. The time interval between diagnosis of HSP and endothelial study was at least 6 months. Endothelial function evaluation was assessed by a noninvasive technology named peripheral arterial tonometry, using an ENDO_PAT device. The device measures blood flow in the limb, in response to arterial occlusion as an index of endothelial function, Reactive Hyperemic Index (RHI). Endothelial function was compared to known normal values of existing control group consisting of 23 healthy children and adolescents. Results: Nineteen children and adolescents (M:F 8/11) age (3.9 ± 13.5 years) with history of HSP were included in the study. Endothelial function was compared to that of a known control group comprising of 23 healthy children and adolescents of the same age group and M:F ratio. There was no difference in RHI levels between the children with diagnosis of HSP and the control group (1.8 ± 0.7 vs. 1.9 ± 0.35 p = 0.7). For patients with HSP we used multi variant regression models to evaluate relation between RHI and different variables the final model include smoking that have negative effect (β = (−1.042), P = 0.31) and, period of time from diagnosis to time of evaluation that have positive effect (β = 0.139, P = 0.003) (R2 = 0.476). When we excluded two patients with exceptional level of RHI from the study a higher correlation was found between those variables and RHI (R2 = 0.76). RHI levels were significantly higher in patients that endothelial function was measured more than 6 years after diagnosis of HSP compared to the rest of the group (1.98 ± 0.74 vs 1.38 ± 0.43 P = 0.037). Conclusion: These results suggest that HSP cause endothelial dysfunction that improves with time. The influence of the endothelial dysfunction on the long term chances of developing atherosclerosis has still to be determined.