Search

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.

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+.

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 Recurrent fever syndromes have a significant impact on health-related quality of life (HRQoL).1 Canakinumab (CAN) has demonstrated efficacy and safety in patients with colchicine-resistant familial Mediterranean fever (crFMF), hyper-immunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS) in the pivotal, Phase 3, CLUSTER trial (NCT02059291),2 but there are limited published data on the impact of CAN on the HRQoL, work/school and social life of these patients. Objectives To evaluate effect of CAN on HRQoL, work/school and social life of patients in the 3 disease cohorts (crFMF, HIDS/MKD, and TRAPS) in a double blinded randomised study. Methods The detailed study design was reported previously.2 The HRQoL of patients treated with CAN was assessed at Baseline (BL), Week 17 (Wk17) and Week 41 (Wk41) in patients who fully responded (absence of flares), either to 150 mg q4w CAN, or to 300 mg q4w CAN after up dosing. Methods used were the Child Health Questionnaire (CHQ)-PF50 physical (PhS) and psychosocial (PsS) summary scores (children >5– Results Patients showed a high impairment of HRQoL at baseline in all 3 cohorts (crFMF n=31, HIDS/MKD n=37 and TRAPS n=22). At Wk17, a moderate to large treatment effect, either with 150 mg or 300 mg q4w CAN, was observed by an improvement in the CHQ-PF50 PhS and PsS (increased >5), SF-12 PCS (increased >5) and SDS scores (decreased below 2). At Wk41, the number of patients on CAN was limited (crFMF n=9, HIDS/MKD n=6 and TRAPS n=4) due to the design of the trial (randomised withdrawal part). For the patients who remained on CAN, the improvement in HRQoL, work/school and social life was sustained. Conclusion Treatment with CAN led to sustained improvement of HRQoL, work/school and social life in patients with crFMF, HIDS/MKD and TRAPS. References [1] Sahin, et al. Eur Rev Med Pharmacol Sci. 2013;17:958–963. [2] De Benedetti, et al. NEJM 2018;378:1908–1990. Disclosure of Interests Helen J. Lachmann Grant/research support from: SOBI, Novartis, Consultant for: Novartis, Takeda, Speakers bureau: SOBI. Novartis, Bernard Lauwerys: None declared, Paivi Miettunen: None declared, Tilmann Kallinich Grant/research support from: Novartis, Speakers bureau: Sobi, Roche, Novartis, CLB, Gerd Horneff: None declared, Riva Brik: None declared, Rafaelle Manna: None declared, Sara Murias: None declared, Sinisa Savic Grant/research support from: Novartis and Sobi, Serge Smeets Employee of: Novartis, Fabrizio De Benedetti Grant/research support from: Abbvie, SOBI, Novimmune, Roche, Novartis, Sanofi, Pfizer, Anna Simon: None declared

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

BACKGROUND: Diagnosis of Periodic Fever, Aphthous stomatitis, Pharyngitis and Cervical Adenitis (PFAPA) syndrome is currently based on the modified Marshall's criteria, but no validated evidence based classification criteria for PFAPA has been established so far. METHODS: A multistep process, based on the Delphi and Nominal Group Technique was conducted. After 2 rounds of e-mail Delphi survey involving 21 experts in autoinflammation we obtained a list of variables that were discussed in an International Consensus Conference. Variables reaching the 80% of consensus between participants were included in the new classification criteria. In the second phase the new classification criteria and the modified Marshall's criteria were applied on a cohort of 80 pediatric PFAPA patients to compare their performance. RESULTS: The Delphi Survey was sent to 22 participants, 21 accepted to participate. Thirty variables were obtained from the survey and have been discussed at the Consensus Conference. Through the Nominal Group Technique we obtained a new set of classification criteria. These criteria were more restrictive in respect to the modified Marshall's criteria when applied on our cohort of patients. CONCLUSION: Our work led us to identify a new set of classification criteria for PFAPA syndrome, but they resulted to be too restrictive to be applied in daily clinical practice for the diagnosis of PFAPA. ispartof: PEDIATRIC RHEUMATOLOGY vol:16 issue:1 ispartof: location:England status: published

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.

Juvenile Idiopathic Arthritis (JIA) includes a group of systemic inflammatory disorders of unknown etiology for which no curative treatment currently exists. The traditional treatment for these disorders which includes the use of NSAIDs and disease modifying anti-rheumatic drugs (DMRADs) is only effective in a subset of patients. Recent advances in understanding the pathophysiology of the inflammatory response, have led to the development of a new class of medications, termed biologic agents which are capable of selectively inhibiting the principal mediators of inflammation. The introduction of biologic drugs has opened a new era in the treatment of rheumatic disorders in children. In this review we describe the characteristics of the currently available biologic agents in Israel, and the updated information regarding indications, efficacy and the safety of these drugs in pediatric patients. Disclosure: Consultant and participating in clinical trials for Novartis com.

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.

Respiratory disease is a common reason for hospitalization and mortality in persons with severe intellectual and developmental disability. Capnography is the measurement and numerical display of end-tidal carbon dioxide (EtCO2). This was a prospective, case controlled, cross sectional study to assess differences of baseline EtCO2 values between neurologically impaired patients and healthy individuals. 86 neurologically impaired patients were evaluated in the study group. Their mean age ± SD was 25.65 ± 10.48 years with 41% males. 53 healthy children and young adults were evaluated in the control group. Their mean age ± SD was 21.95 ± 10.38 years with 54.7% males. Patients with severe neurological impairment had higher baseline EtCO2 values than healthy individuals. Kyphoscoliosis and the use of antipsychotic drugs were the major factors to increase EtCO2 levels. Knowing the patient's baseline EtCO2 value, as well as baseline oximetry, could guide treatment decisions, when assessing the patient's oxygenation and ventilation during acute respiratory illness, and can potentially prevent unnecessary laboratory and imaging investigations as well as over treatment. Future research can shed light on the utility of capnometry and clinical implications of higher baseline EtCO2 values among neurologically impaired patients.

Objective The myeloid-related proteins 8 and 14 (MRP-8/MRP-14) and neutrophil-derived S100A12 are biomarkers of inflammation. They can be used to determine the relapse risk in patients with juvenile idiopathic arthritis (JIA) after stopping antiinflammatory treatment. In this study, we tested the performance of different enzyme-linked immunosorbent assays (ELISAs) in order to validate systems available for routine use. Methods MRP-8/MRP-14 and S100A12 serum concentrations of 188 JIA patients in remission were analyzed. Commercially available test systems were compared to experimental ELISAs established in house. The ability of the assays to identify JIA patients at risk for relapse was analyzed. Results For MRP-8/MRP-14, the PhiCal Calprotectin and Buhlmann MRP8/14 Calprotectin ELISAs revealed hazard ratios of 2.3 and 2.1, respectively. For S100A12, the CircuLex S100A12/EN-RAGE ELISA revealed a hazard ratio of 3.1. The commercial assays allowed a JIA relapse prediction that was at least comparable to the experimental ELISAs. Conclusion For the prediction of JIA relapse after stopping medication, the biomarkers MRP-8/MRP-14 and S100A12 can be determined by using assays that are available for routine use. The tested commercial MRP-8/MRP-14 and S100A12 ELISAs showed a performance comparable to well-established experimental ELISA protocols when assay-specific cutoffs for the indication of relapse prediction are thoroughly applied.

OBJECTIVES: The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. METHODS: We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. RESULTS: Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. CONCLUSION: We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.

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

Background Acute bronchiolitis is the most frequent lower respiratory tract infection in infants. Only small subsets of patients develop severe disease resulting in hospitalization despite having no identifiable risk factors. There is still a debate as to the role of capnometry in assessing ventilation in children with acute respiratory distress, and bronchiolitis in particular. Methods This was a prospective, single blind cohort study in which children younger than two years presenting to the emergency department (ED) with bronchiolitis were included. Our primary outcome was the correlation between the end tidal CO2 (EtCO 2 ) and the clinical decision of hospital admission and discharge. Our secondary outcome measure was the correlation of EtCO 2 upon arrival to the ED and clinical measures of bronchiolitis severity. Finally, by using multivariate models, we looked for other parameters that could contribute to the prediction of illness severity. Results One hundred and fourteen children with bronchiolitis were evaluated. Their median EtCO 2 upon arrival to the ED was 34 mmHg (range 24–65 mmHg). EtCO 2 values upon admission or discharge were not statistically different among patients who were hospitalized and among those who were discharged from the ED. Among admitted patients, we found no correlation between capnometry readings at admission and number of oxygen desaturation days, nor with the length of hospitalization. Wang clinical respiratory severity score was found, by using multivariate models, to predict nasogastric tube need, oxygen desaturation days, and length of hospitalization. Conclusion Capnometry readings upon arrival to the ED did not predict hospital admission or hospital discharge eligibility. Among hospitalized patients, EtCO 2 did not correlate with the evaluated disease severity measures. Wang score was found to be the most consistent predictor of significant outcomes.

Juvenile idiopathic arthritis (JIA) is the most common autoimmune inflammatory disease in children; joint inflammation is the hallmark of the disease. Thirty-five children with JIA were studied, of whom 26 had active disease and 14 were receiving anti-TNF therapy (5 with Infliximab, 9 with Etanercept). Sixteen healthy controls also were studied. Saliva samples were obtained for analysis of anti-oxidant status, metalloproteinases (MMPs) and sialochemistry. The total antioxidant status was significantly higher in the saliva of all JIA patients, whether treated (P = 0.014) or not treated (P = 0.038) with anti-TNF agents. The increase in antioxidant status (TAS) in the saliva of the active patients was nearly two times higher than that of non-active patients (P = 0.01). MMP levels were significantly lower in JIA patients than in controls. MMP-9, MMP-3 and MMP-2 were lower in JIA patients without anti-TNF treatment by 36.7% (P = 0.01), 30.0% (P = 0.0001) and 10.7% (P = 0.0001), respectively. A greater reduction in MMP levels was observed in the group of patients treated with anti-TNF drugs: MMP-9, MMP-3 and MMP-2 were lower than in controls by 51.1% (P = 0.0001), 61.5% (P = 0.0001) and 55.4% (P = 0.0001), respectively. Children with JIA exhibited a significantly higher salivary antioxidant activity and significantly lower MMP levels. Anti-TNF treatment was associated with a further decrease in MMP levels in the saliva of JIA patients while an active state of JIA was associated with a further increase in the salivary antioxidant activity. Anti-TNF treatment may modulate the degradation process during the course of arthritis by inhibition of the activity of MMP.

The aim of this study was to describe the clinical manifestations and outcomes of a national cohort of childhood systemic lupus erythematosus (cSLE). All cases of cSLE registered in the Israeli national registry of children with rheumatic diseases between 1987–2003 were examined for disease activity and damage by the SLE disease activity index (SLEDAI) and SLE collaborating clinics/American College of Rheumatology (SLICC/ACR) damage index. Demographic, clinical, laboratory and treatment factors were analysed for their effect on the outcome. One-hundred and two patients were identified, 81% females, with a mean age at diagnosis of 13.3 ± 2.6 years. The mean SLEDAI score was 17.2 ± 9.0 (range 2–60). Fifty four patients were followed for at least five years. The mean SLEDAI decreased to 7.6 ± 6.3 (0–29) and the mean SLICC/ACR damage index was 0.7 ± 1.6 (0–8). Five patients developed chronic renal failure. No patients died. No factors were found to be significantly associated with the outcome except the initial SLEDAI score. The five-year outcome of our national cSLE cohort was good; with relatively low activity and minimal damage in most patients. The initial SLEDAI predicted the development of late damage.

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.

Objectives Based on the fact that Henoch-Schonlein purpura (HSP) occurs in approximately 5% of persons with familial Mediterranean fever (FMF), we assessed the prevalence and significance of FMF gene mutations in children with one or more episodes of HSP. Study design Thirty-four boys and 18 girls treated for HSP at Rambam Medical Center were interviewed and asked to donate blood. Mean age at disease onset was 6.7±2. 4 years, and mean follow-up was 3.8±1.3 years. Six predominant mutations (M694V, M680I, M694I, V726A, K695R, E148Q) in the MEFV gene were studied. Results Nine heterozygotes, three homozygotes and two compound heterozygotes, were identified. Altogether, five persons (10%) carried two mutated MEFV alleles, a number significantly exceeding that determined for the general Israeli population (1%–2%). Of these, three displayed genotypes associated with a mild form of disease (M694V/E148Q and V726A/V726A), and two had genotypes normally observed in disease-free persons (E148Q/K695R and E148Q/ E148Q). Conclusions Occult FMF cases much more numerous than expected were identified among children presenting with HSP. Such children should be closely monitored for renal complications, and treatment with colchicine should be considered.

Airway obstruction is common among patients with craniosynostosis. We describe an infant with a clinical and genetic diagnosis of Crouzon syndrome who presented with respiratory distress and heart murmur in early neonatal life. Cardiac evaluation revealed absent pulmonary valve syndrome. She needed intubation at age 1 month, and repeated trials of extubation failed because of marked respiratory distress, stridor, and severe expiratory obstruction and wheezing. Correction of her cardiac anomaly did not relieve her respiratory distress; only after endobronchial stenting and tracheostomy was it possible to gradually wean her from mechanical ventilation. This case report demonstrates and discusses the different causes of airway obstruction in Crouzon syndrome and the morbidity and mortality that can result from pulmonary involvement in this craniosynostotic syndrome. It also demonstrates the difficult therapeutic challenge created by the combination of cardiopulmonary abnormalities in Crouzon patients.

Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterised by recurring attacks of fever and serositis. Five sequence alterations (M694V, V726A, M680I, M694I and E148Q), in the MEFV gene, account for the majority of FMF chromosomes. The wide clinical variability of the disease has been related to MEFV allelic heterogeneity. M694V homozygotes have a severe form of the disease. Mutations E148Q and V726A have reduced penetrance. The clinical features, associated with the M680I and the complex V726A-E148Q allele, are not well defined. This study aims to further characterise the phenotypic profile associated with the major MEFV mutations. We investigated 220 FMF patients, in whom both FMF alleles have been identified, and found that different genotypes are characterised by a specific allelic related clinical profile and penetrance. Homozygotes for the M694V mutation and the complex V726A-E148Q allele are the most severely affected and often endure renal amyloidosis. Homozygotes for the M680I and V726A alleles and compound heterozygotes for either the M694V or the V726A-E148Q alleles in combination with either the E148Q, the V726A or the M680I alleles are significantly less severely affected. The morbididity associated with the complex V726A-E148Q allele by far outweighs that associated with the V726A allele, bearing evidence to the fact that the E148Q mutation is not a benign polymorphism. These findings increase our understanding of the role of allelic variability in disease expression.

The objective of this study is to examine if the B-type natriuretic peptide (BNP) can be used in diagnosing heart failure (HF) in children with congenital heart disease (CHD) who present to the emergency department (ED) with acute bronchiolitis.A prospective cohort single-group study of children with CHD and respiratory syncytial virus bronchiolitis was conducted in a pediatric ED. The reference standard for the presence of HF was the clinical and echocardiographic assessment of a pediatric cardiologist blinded to the BNP test results.Eighteen cases were diagnosed, 7 (39%) had acute HF and 11 (61%) did not have acute HF. Patients with HF had a higher level of BNP compared with patients who did not have HF (783 pg/mL [interquartile range, 70-1345] vs 59 pg/mL [interquartile range, 23-90]; P.013). A BNP level of 95 pg/mL was the optimal cutoff point, having a sensitivity of 0.71 (95% confidence interval, 0.29-0.96) and a specificity of 0.91 (95% confidence interval, 0.58-0.99).The results of this small study suggest that the BNP test can be useful to ascertain the presence of HF in children with CHD who present to the ED with respiratory syncytial virus bronchiolitis.

FMF is widely distributed in populations inhabiting the Mediterranean basin. It is mainly attributed to five founder mutations (M680I, M694V, M694I, V726A, E148Q) in the MEFV gene. The frequencies and distribution of these mutations in 146 FMF patients, of Arab and Jewish descent, were compared to that observed in 1173 healthy individuals of pertinent ethnic groups. Five mutations accounted for 91% of FMF chromosomes in our patients. Mutation M694V, predominant in North African Jews, was observed in all patients other than Ashkenazi Jews; mutation V726A was prevalent among all patients other than North African Jews; mutations M694I and M680I were mainly confined to Arab patients. Overall carrier rates, for four mutations (M680I, M694V, V726A, E148Q), were extremely high in our healthy cohort composed of Ashkenazi (n=407); Moroccan (n=243); Iraqi Jews (n=205); and Muslim Arabs (n=318); calculated at 1 : 4.5; 1 : 4.7; 1 : 3.5 and 1 : 4.3 respectively. The V726A allele prevalent among Ashkenazi and Iraqi Jews and Muslim Arabs (carrier rates: 7.4, 12.8 and 7.3%, respectively) was not found among Moroccan Jews. The M694V allele detected among Moroccan and Iraqi Jews and Muslim Arabs (carrier rates 11.1, 2.9 and 0.6%, respectively) was not observed among Ashkenazim. The overall frequency of mutations V726A and E148Q in Ashkenazim, Iraqi Jews and Arabs indicates that the bulk of individuals that comply with the genetic definition of FMF remain asymptomatic.

Ibuprofen is as effective as paracetamol (acetaminophen) as an antipyretic and analgesic agent in paediatric patients. Ibuprofen is considered to be well tolerated; however, there are reports on gastrointestinal bleeding or renal adverse effects among children treated with ibuprofen. Oral ibuprofen suspension was recently registered and approved by the Ministry of Health in Israel as an antipyretic and analgesic agent. Before distribution of the drug to pharmacies, we aimed to follow possible adverse effects among children receiving ibuprofen suspension in several paediatric wards and clinics. Children with fever needing antipyretic medication received ibuprofen oral suspension 5 to 10 mg/kg/dose. In each case the age of the patient, gender, diagnosis, number of ibuprofen doses, duration of treatment and any adverse reactions were reported. 1564 children from 14 paediatric wards (11 hospitals) and from five paediatric and family clinics participated in the study; 882 males and 682 females. The patients, aged 3.6 ± 4.2 years (range 1 month to 16.5 years), received 2.4 ± 3 (range 1 to 22) doses of ibuprofen suspension for 1.56 ± 2.11 (range 1 to 20) days. Adverse reactions were reported among 26 patients (1.66%) [95% confidence interval (CI) 1.1–2.4]; 18 children (1.15%) [95% CI 0.7–1.8] vomited immediately after the administration of the drug and it was not readministered. Two children (0.12%) [95% CI 0.02–0.46] had abdominal pain that resolved spontaneously, two patients reported nausea, and two other children had diarrhoea. Eight children (0.51%) reported experiencing a ‘bitter taste’ from the medication, of whom one patient discontinued the medication while the other seven continued it. The adverse reactions following administration of oral ibuprofen suspension reported in our study were low in frequency, mild and disappeared spontaneously. However, continuing reporting on its tolerability is needed.

Canakinumab (CAN), a selective, fully human, anti-interleukin-1β monoclonal antibody, has been shown to be efficacious in SJIA patients (pts) in 2 phase 3 trials: Trial 1 (4-wk, randomized placebo [PBO]-controlled) and Trial 2 (open-label CAN treatment [Part 1] followed by a randomized PBO-controlled withdrawal phase [Part 2]). In Trial 1, statistically significantly more CAN than PBO group pts achieved an adapted pediatric ACR 30 response and in Trial 2, CAN allowed successful reduction/discontinuation of steroids and significantly reduced risk of flare. Safety profile of CAN was in line with expectations for a biologic agent in active SJIA. The persistent disabling features of SJIA and chronic pain can have a negative impact on health-related quality of life (hrqol). These outcomes were evaluated in the CAN phase 3 program.

Tumor necrosis factor (TNF) blockade has been used successfully to treat a number of rheumatic disorders that have a substantial burden of illness. In children, the TNF antagonists are used mainly for the treatment of juvenile idiopathic arthritis (JIA). There are, however, a variety of rare systemic inflammatory diseases, in which TNF blockade appears promising. Preliminary data in adults suggest that several forms of vasculitis appear to be responsive to TNF antagonists-Behcet's disease, polyarteritis nodosa, Wegener granulomatosis, among others. Some of them respond better to infliximab, a chimeric monoclonal anti-TNF antibody, than to etanercept, a recombinant p75 TNF receptor. We describe our limited experience with infliximab in the treatment of three children with rare vasculitic conditions.

We performed a prospective, randomized, open-label equivalence study comparing the use of naproxen to aspirin in 33 patients with rheumatic fever. The mean time until resolution of arthritis was 2.9+/-2.9 days in both groups. Liver enzyme elevations were more frequent in the aspirin group (P=.002). We conclude that naproxen is as effective, is easier to use, and is safer than aspirin in the treatment of the arthritis of rheumatic fever.

This study sought to determine the appropriate starting dose of colchicine in children aged 2 to 4 years with familial Mediterranean fever (FMF) based on steady-state pharmacokinetics in pediatric patients with FMF from 2 to less than 16 years and adult patients with FMF from 16 to 65 years. Outpatients received colchicine for 90 days starting with a fixed dose for 14 days (blood sampling days 14 and 15). After starting doses of colchicine (0.6 mg/day [2 to less than 4 years], 0.9 mg/day [from 4 to less than 6 years], 0.9 mg/day [from 6 to less than 12 years], 1.2 mg/day [from 12 to less than 16 years], and 1.2 mg/day [from 16 to less than 65 years]), the observed steady-state pharmacokinetic parameters were comparable across age groups, despite the higher doses of colchicine on a mg/kg/day basis in the younger age groups. An exception occurred with once-daily colchicine, whereby mean Cmax for colchicine was higher in patients 4 to less than 6 years (9.4 ng/mL) compared with the younger and older age groups (6.1-6.7 ng/mL). Mean AUC0?24h values in children 2 to less than 4, 6 to less than 12, and 12 to less than 16 years were similar to those in adults. However, mean AUC0?24h values in children 4 to less than 6 years were 25 percent higher than those observed in adults. The results show that the recommended starting dose for children 2-4 years and 4-6 years should be 0.6 mg/day (half the US adult dose). Children aged 6 to less than 12 years should receive 0.9 mg/day (i.e. three-quarters of the US adult dose). The safety of colchicine in children 2 to less than 4 years was comparable to that in older children and adults.

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.

We report on a baby girl with congenital muscular dystrophy (CMD) with neurological abnormalities (“CMD Plus” condition), who also had Hirschsprung disease. This association may indicate a category of congenital muscular dystrophy with involvement of the visceral nervous system. We propose that Hirschsprung disease be added to the list of anomalies pertaining to the “CMD Plus” array, and that CMD should be considered when Hirschsprung disease occurs with central nervous system anomalies. © 1993 Wiley-Liss, Inc.

Juvenile dermatomyositis is an inflammatory disease of unknown etiology that primarily affects skin and muscles. The pathognomonic Gottron's sign consists of symmetric macules and papules on the dorsal aspect of the interphalangeal joints and exterior areas of the big joints. A periorbital violaceous (heliotrope) skin rash is also characteristic. There may be a discordance in time of presentation of the skin and muscle disease, and a small subset of patients apparently do not develop muscle disease at all. The absence of muscle involvement is termed 'amyopathic dermatomyositis.'We describe two children who presented with the characteristic rash of juvenile dermatomyositis but with no clinical evidence of muscle involvement. One developed muscle weakness 3 years later. Neither patient had a full muscle work-up at the onset of the disease, which left questions about diagnoses and whether or not there may have been subtle muscle involvement. On the basis of our literature review, the outcome of these patients is uncertain, although it appears that myositis develops in many, maybe most, affected children. We suggest that in the absence of muscle disease, application of sunscreen and administration of hydroxychloroquine sulfate may ameliorate the rash. More aggressive treatment will need to be given when muscle involvement can be demonstrated.

EULAR/PRINTO/PRES Objectives To validate the previously proposed classification criteria for Henoch-Schonlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA).Methods Step 1: retrospective/prospective webdata collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis

PFAPA is a periodic fever disease, of unknown etiology, characterized by aphthous stomatitis, pharyngitis and cervical adenitis. To inquire whether genes implicated in other auto-inflammatory diseases might be involved in its pathogenesis, predominant mutations in the genes causing familial Mediterranean fever, TNF receptor-associated periodic fever syndrome, Crohn's disease and Muckel-Wells syndrome were analyzed in PFAPA patients. Patients (n = 57) with PFAPA, according to previously published criteria were recruited, at the Meyer Children Hospital during 2006-2007. Clinical information was complemented during physicians-parents encounter. Predominant mutations in MEFV, TNF1rA, CARD15/NOD2 and NLRP3 genes were tested. Mean age at diagnosis was 30.64 +/- 16.4 months. Boys (n = 33; 58%) were diagnosed earlier than girls (n = 21; 42%) at 26.18 +/- 13.83 and 36.41 +/- 18.32 months, respectively (P = 0.05). Fifteen patients (27%) carried an MEFV mutation; two patients (3.6%) a CARD15 mutation, one patient (1.8%) a variance in TNF1rA and another had both an MEFV and a CARD15 mutation. Clinical symptoms were equally manifested in carriers and non-carriers. The high carrier rate of MEFV mutations in our PFAPA cases compares well with that of the general population in Israel. It is debated whether MEFV mutations, when mediated by the presence of additional modifiers, may expose a transient fever condition, namely PFAPA.

Objective:To assess whether the removal of aids/devices and/or help from another person in the Childhood Health Assessment Questionnaire (C-HAQ) leads to a significant change in the disability index (DI) score and responsiveness in juvenile idiopathic arthritis (JIA).Methods:Changes in the C-HAQ DI score in a cross-sectional sample of 2663 children with JIA and in 530 active patients with JIA in a trial of methotrexate (MTX) were compared.Results:Patients in the MTX trial had higher disease activity and disability than the cross-sectional sample. The frequency of aids/devices (range 1.2–10.2%) was similar between the two samples, while help (range 5.3–38.1%) was more frequently used in the MTX group. Correlation between disease severity variables and the two different C-HAQ DI scoring methods did not change substantially. There was a decrease in the C-HAQ DI score for both the cross-sectional (mean score from 0.64 with the original method to 0.54 without aids/devices and help, pConclusion:The removal of aids/devices and help from the C-HAQ does not alter the interpretation of disability at a group level. The simplified C-HAQ is a more feasible and valid alternative for the evaluation of disability in patients with JIA.

Prolidase deficiency (PD) is a rare, pan-ethnic, autosomal recessive disease with a broad phenotypic spectrum. Seventeen causative mutations in the PEPD gene have been reported worldwide. The purpose of this study is to characterize, clinically and molecularly, 20 prolidase deficient patients of Arab Moslem and Druze origin from 10 kindreds residing in northern Israel. All PD patients manifested developmental delay and facial dysmorphism. Typical PD dermatological symptoms, splenomegaly, and recurrent respiratory infections presented in varying degrees. Two patients had systemic lupus erythematosus (SLE), and one a novel cystic fibrosis phenotype. Direct DNA sequencing revealed two novel missense mutations, A212P and L368R. In addition, a previously reported S202F mutation was detected in 17 patients from seven Druze and three Arab Moslem kindreds. Patients homozygous for the S202F mutation manifest considerable interfamilial and intrafamilial phenotypic variability. The high prevalence of this mutation among Arab Moslems and Druze residing in northern Israel, and the presence of an identical haplotype along 500,000 bp in patients and their parents, suggests a founder event tracing back to before the breakaway of the Druze from mainstream Moslem society.

Open Access Poster presentation Does incorporation of aids/devices and help, make a difference in the childhood health assessment questionnaire disability index? Analysis from the printo juvenile idiopathic arthritis database C Saad-Magalhaes*, A Pistorio, A Ravelli, R Brik, D Mihaylova, R Ten Cate, B Andersson-Gare, V Ferriani, K Minden, P Hashkes, M Rygge, MJ Sauvain, H Venning, A Martini and Ruperto for the Paediatric Rheumatology International Trials Organisation (PRINTO) N

The presence of IgA rheumatoid factor (IgA-RF) has been correlated with severe joint disease in adult rheumatoid arthritis (RA), but IgA-RF has not been reported in juvenile rheumatoid arthritis (JRA). In the present study, IgA-RF was assayed by an enzyme-linked immunosorbent assay and was found in the sera of 14 of 24 children (58%) with active polyarticular JRA. The presence of IgA-RF correlated with the degree of functional disability. In contrast, IgA-RF was not found in the sera of systemic-onset disease patients, regardless of the degree of dysfunction. IgA-RF was detected in only 1 patient with pauciarticular disease, despite the fact that several patients in this group had severe disease. The presence of IgA-RF in polyarticular JRA did not correlate with serum IgA levels, but did correlate with the presence and the level of serum IgM-RF. Thus, the presence of IgA-RF appears to be specific for polyarticular JRA, and shows a correlation with severe disease in this group.