A novel loss-of-function mutation in LACC1 underlies hereditary juvenile arthritis with extended intra-familial phenotypic heterogeneity.

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.

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome - Is It Related to Ethnicity? An Israeli Multicenter Cohort Study.

OBJECTIVES: To evaluate the ethnic distribution of Israeli patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA). STUDY DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

Familial Mediterranean Fever Is Commonly Diagnosed in Children in Israel with Periodic Fever Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome.

OBJECTIVES: 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). STUDY DESIGN: 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. RESULTS: 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). CONCLUSION: 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.

Japanese scoring systems to predict resistance to intravenous immunoglobulin in Kawasaki disease were unreliable for Caucasian Israeli children.

AIM: This study assessed the validity of using established Japanese risk scoring methods to predict intravenous immunoglobulin (IVIG) resistance to Kawasaki disease in Israeli children. METHODS: We reviewed the medical records of 282 patients (70% male) with Kawasaki disease from six Israeli medical centres between 2004 and 2013. Their mean age was 2.5 years. The risk scores were calculated using the Kobayashi, Sano and Egami scoring methods and analysed to determine whether a higher risk score predicted IVIG resistance in this population. Factors that predicted a lack of response to the initial IVIG dose were identified. RESULTS: We found that 18% did not respond to the first IVIG dose. The three scoring methods were unable to reliably predict IVIG resistance, with sensitivities of 23%-32% and specificities of 67%-87%. Calculating a predictive score that was specific for this population was also unsuccessful. The factors that predicted a lacked of response to the first IVIG dose included low albumin, elevated total bilirubin and ethnicity. CONCLUSION: The established risk scoring methods created for Japanese populations with Kawasaki disease were not suitable for predicting IVIG resistance in Caucasian Israeli children, and we were unable to create a specific scoring method that was able to do this.

High-dose aspirin for Kawasaki disease: outdated myth or effective aid?

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[BIOLOGIC THERAPY FOR JUVENILE IDIOPATHIC ARTHRITIS].

INTRODUCTION: 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.

[EARLY DETECTION OF ENDOTHELIAL DYSFUNCTION IN CHILDREN WITH AUTOIMMUNE DISEASES BY A NOVEL NONINVASIVE TECHNIQUE].

INTRODUCTION: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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 (p <0.05). 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). CONCLUSIONS: 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.

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1ß monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients.

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.

Diagnosing heart failure in children with congenital heart disease and respiratory syncytial virus bronchiolitis.

OBJECTIVE: 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. METHODS: 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. 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). CONCLUSION: 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.

Atypical Henoch-Schonlein purpura: a forerunner of familial Mediterranean fever.

Insuception is the most common cause of intestinal obstruction in early childhood. The cause of most intussusceptions is unknown but it can complicate the course of Henoch-Schonlein purpura (HSP) as a result of the vasculitic process. Familial Mediterranean fever (FMF), a common disease in Israel, is also associated with HSP. In a few patients, particularly in children, HSP has been reported to precede the diagnosis of FMF. We describe two patients with an unusual clinical course of severe abdominal pain as a result of intusucception. The correlation between intusucception, HSP and FMF are discussed.

Familial Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome; Is It a Separate Disease?

Introduction: Periodic 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. Objective: To identify demographic and clinical differences between patients with PFAPA and a positive family history (FH+) as compared to those 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%) 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. Results: The 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). Conclusions: Our 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+.

Salivary antioxidants and metalloproteinases in juvenile idiopathic arthritis.

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.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria.

OBJECTIVES: To validate the previously proposed classification criteria for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). METHODS: Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis

MEFV, TNF1rA, CARD15 and NLRP3 mutation analysis in PFAPA.

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.

A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability.

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.

Is palindromic rheumatism amongst children a benign disease?

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.

Towards a new set of classification criteria for PFAPA syndrome.

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.

Tumor necrosis factor blockade in the management of children with orphan diseases.

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.

Endothelial function in children with a history of henoch schonlein purpura.

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.