Approximately 20% of patients withy systemic lupus erythematosus (SLE) have disease which begins in childhood. Several series have reported that childhood-onset SLE (cSLE) is often more severe than adult disease with more pronounced clinical, immunologic and serologic abnormalities. In particular, renal and central nervous system (CNS) involvement tend to be more severe in pediatric than in adult patients. The morbidity and mortality associated with SLE result from a combination of severe organ damage from disease, infection or side effects and complications of treatment. Since neither disease activity nor disease damage in SLE can be measured directly with any clinical sign or laboratory value, a number of disease indices have been developed that allow standardized comparison of SLE cohorts. Disease activity indices including SLEDAI, SLAM, BILAG and ECLAM have been validated in cSLE and none appears superior. The SLICC damage index was developed to measure permanent disease damage in adults with SLE and was subsequently validated in cSLE. It has been suggested that pediatric version should include additional domains addressing pediatric specific issues such as growth failure and delayed puberty, but both indices are reversible and they do not fulfil the definition of nonreversible organ damage. Several predictors (risk factors) have been linked with poor prognosis in cSLE. Using the SLICC-DI scoring system for damage, it has been demonstrated that renal and/or CNS disease represent major determinants of morbidity and mortality in cSLE. Diffuse proliferative glomerulonephritis is most consistently linked with a poor prognosis if associated with hypertension. Other suggested risk factors associated with poor prognosis in cSLE include acute thrombocytopenia, young age at diagnosis, male sex and nonwhite (black, Asian and Hispanic) ethnicity. The presence of antiphospholipid antibodies may predispose to disease damage by increasing the risk for recurrent venous thrombosis, stroke and thrombocytopenia. Similar to previous adult studies, it has been shown in cSLE that cumulative disease activity over time results in increased damage, and early introduction of therapy with immunosuppressive drugs might improve the outcome by preventing permanent damage. The exact impact of corticosteroid therapy on increased disease damage is still controversial, but patients may benefit from judicious use of corticosteroid with refined tapering schedules and early introduction of steroid-sparing drugs. It has been also demonstrated that frequent occurrence of severe, major disease flares requiring intravenous cyclophosphamide treatment represent a risk factor for damage, but not mild or moderate flares. Disclosure of Interest None Declared

Neuropsychiatric involvement is one of the most common features of childhood-onset systemic lupus erythematosus (cSLE) occurring in 20 to 95% of patients. The large variation in frequency of neuropsychiatric manifestations reported in cSLE is the result of differing case definitions and the methods used for evaluation. The majority of patients with neuropsychiatric involvement have the initial signs and symptoms early in the course of the disease and approximately 25% develop initial neuropsychiatric manifestations more than 2 years after disease onset. There have been few comprehensive studies evaluating neuropsychiatric disease in cSLE. In general, central nervous system involvement appears to be more severe in children than in adults and cSLE is associated with higher accrual of permanent organ damage. The most common neuropsychiatric manifestation in cSLE is headache occurring in approximately 50% of patients. Neurocognitive deficits in cSLE ranges from concentration difficulties, a decrease in school performance to frank confusion and coma. Since there are no validated clinical or research neuropsychological testing for children, it is particularly difficult to determine subtle neurocognitive impairment in cSLE. Cerebrovascular disease occurs in up to 30% of patients with neuropsychiatric involvement and is usually associated with the presence of antiphospholipid antibodies. Antiphospholipid antibodies have been associated also with other neuropsychiatric manifestations, in particular movement disorders (chorea), seizures, psychosis and transverse myelopathy. These latter manifestations are likely the result of a nonthrombotic, immune-mediated mechanism rather than thrombosis. Involvement of peripheral nervous system has been infrequently described in cSLE, mainly as isolated case reports only. The diagnosis of neuropsychiatric involvement in cSLE is often difficult, as both focal and diffuse manifestations may occur and there is no gold standard for diagnosis. A high index of clinical suspicion, in addition to laboratory and neuroimaging findings may support the diagnosis. It is important to exclude other causes such as infection, hypertension or metabolic abnormalities associated with neuropsychiatric signs and symptoms. The management of patients with neuropsychiatric cSLE requires interdisciplinary approach and includes symptomatic and immunosuppressive medications. In patients with severe neuropsychiatric involvement a combination therapy with high-dose steroids and cyclophosphamide is usually required. Psychotropic medications and supportive non-pharmacological approaches are frequently required in patients with psychiatric disorders and cognitive dysfunction. In the future, it is expected that novel biomarkers and advanced neuroimaging modalities will provide better understanding of the underlying mechanisms of neuropsychiatric involvement in cSLE and help guide therapeutic decisions. Disclosure of Interest None Declared

Background Anti drug antibodies are known to alter drug pharmacokinetics, decrease drug efficacy and in rare cases they may also lead to life-threatening anaphylactic or anaphylactoid reactions. Infliximab is a chimeric monoclonal antibody that is due to its variable domains of murine origin often immunogenic for its recipients. Previously, we reported that antibodies to infliximab (ATI) developed in nearly 43% of the pediatric patients with rheumatic diseases that were treated with infliximab. The development of ATI was in all cases associated with decreased infliximab serum trough levels and decreased drug efficacy (Kosmač et al., 2011). Objectives In the present study we analyzed the isotypes (IgG, IgM, IgA and IgE) and in the case of IgG antibodies also the subtypes (IgG1, IgG2, IgG3 and IgG4) of ATI-positive serum samples from pediatric patients treated with infliximab. Methods We compared the isotype-specific binding assay with the more common double antigen bridging assay and used both to analyze 121 serum samples from 21 pediatric patients treated with infliximab. In the 36 serum samples that tested positive for ATI in the isotype-specific binding assay we also used this assay to subsequently determine the isotypes and IgG subtypes of the detected antibodies. Results The predominant ATI isotype was IgG (median [IQR] =60.5% [65.4%]), followed by IgA (35.4% [65.5%]), IgE (0.8% [0.9%]) and IgM (bellow detection). More specifically, the two most represented IgG subtypes were IgG1 and IgG3 (27.9% [52.9%] and 20.4% [38.6%] of total IgG, respectively). However, in the majority of sera tested several different isotypes and subtypes were observed simultaneously and in the cases where high absolute ATI values were observed there was a high proportion of IgG4 (30.6% [13.8%]). Conclusions As expected for T-dependent protein antigens, ATI were predominantly of the IgG isotype. There was a low prevalence of IgE antibodies, also in the cases where patients experienced infusion-related reactions, arguing against the classical type I hypersensitivity. After IgG, the second most prominent anti-infliximab isotype were IgA antibodies, which are generally not regarded as a clinically significant antibody isotype, but may along with IgG4 play an immunoprotective role in the chronic exposure to a specific antigen. Additionally, we found that the isotype-specific binding assay was faster, more sensitive and less influenced by residual drug interference than the more common bridging assay. It is however, more prone to false positive results and should therefore be employed in the screening phase of ADA determination. References Kosmač, M., Avčin, T., Toplak, N., Simonini, G., Cimaz, R. and Čurin Šerbec, V., 2011. Exploring the binding sites of anti-infliximab antibodies in pediatric patients with rheumatic diseases treated with infliximab. Pediatric Research, 69(3), pp. 243-248. Disclosure of Interest None Declared

To propose a common nomenclature to refer to individuals who fulfill the American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE) during childhood or adolescence.

Lupus anticoagulants (LA) were first detected in patients with systemic lupus erythematosus (SLE) in 1952 by Conley and Hartmann.1 They identified patients in whom the activated partial thromboplastin time (APTT) was prolonged and which did not correct on the addition of normal plasma. Although Conley and Hartmann's original description was in association with a haemorrhagic disorder, subsequent reports from the 1960s highlighted patients with thrombotic events in the presence of LA.2 The term ‘lupus anticoagulant’ was introduced by Feinstein and Rapaport in 1972.3 It has, however, caused some confusion because LA tend to be procoagulant in vivo, and most people who test positive for LA do not meet criteria for a diagnosis of SLE.4 LA are a subset of antiphospholipid antibodies (aPL) which also include anticardiolipin antibodies (aCL) and anti-β2 glycoprotein-I (anti-β2GPI) antibodies among others. The clinical significance of these antibodies is their association with venous or arterial thrombosis, or recurrent fetal loss. This association constitutes the antiphospholipid antibody syndrome (APS) for which there are revised classification criteria published in 2006.5 Some features not included in the classification criteria are associated with APS and are more commonly seen in children than adults. These include immune-mediated thrombocytopenia, haemolytic anaemia, migraine, chorea and epilepsy.6 This paper aims to highlight which children should be tested for LA, and the significance of LA if they are detected. LA are a mixture of different immunoglobulins (IgG and IgM) that bind to various protein-phospholipid complexes.4 Targets include β2GPI, prothrombin, protein C and S and factor XI among others.7 In common with other antibodies, LA are produced by B lymphocytes. In the context of SLE, there is a generalised increase in production of autoantibodies. The reasons for production of LA in other contexts are …

Aim: To assess the prevalence of MEFV mutations in Caucasian children with Henoch-Schonlein purpura (HSP) and to investigate a possible association between the two diseases in a population with presumably low incidence of familial Mediterranean fever (FMF). Methods: One hundred and two children diagnosed with HSP between January 2002 and February 2009 were included in the study. Clinical data were obtained from medical charts. Children were tested for 6 common MEFV mutations. To find out the carrier rate of mutations in MEFV gene in Slovenian population a control group of 105 apparently healthy adults was screened. Results: Heterozygous MEFV gene mutations were found in 6% of children with HSP and in 7% of apparently healthy adults. The most common allelic variants found in both groups were as follows: V726A in 5 participants, K695R in 4 participants, E148Q in 3 participants and M694V in 1 participant. No significant differences in HSP clinical picture between the group of children with and without mutations in MEFV were found. HSP patients with MEFV mutations were younger than patients without MEFV mutations. Conclusion: In contrast to previously published researches, MEFV mutations are not more frequent in children with HSP comparing to apparently healthy population and have no influence on the clinical presentation of HSP.

Antibodies against β2-glycoprotein I (anti-β2GPI) are one of the hallmarks of the antiphospholipid syndrome (APS). However, they are heterogenic regarding their epitope specificity, pathogenic mechanisms and their avidity. In the current study we present some outstanding issues about avidity of anti-β2GPI antibodies. Our results confirmed that high avidity anti-β2GPI are associated with thrombosis and APS, while in low avidity anti-β2GPI group non-APS (predominantly systemic lupus erythematosus) patients prevailed.

Objectives This study aimed to describe the long-term outcome and immunological status of children born to mothers with antiphospholipid syndrome, to determine the factors responsible for childhood abnormalities, and to correlate the child's immunological profile with their mothers. Methods A prospective follow-up of a European multicentre cohort was conducted. The follow-up consisted of clinical examination, growth data, neurodevelopmental milestones and antiphospholipid antibodies (APL) screening. Children were examined at 3, 9, 24 months and 5 years. Results 134 children were analysed (female sex in 65 cases, birth weight 3000±500 g, height 48±3 cm). Sixteen per cent had a preterm birth (<37 weeks; n=22), and 14% weighted less than 2500 g at birth (n=19). Neonatal complications were noted in 18 cases (13%), with five infections (4%). During the 5-year follow-up, no thrombosis or systemic lupus erythematosus (SLE) was noted. Four children displayed behavioural abnormalities, which consisted of autism, hyperactive behaviour, feeding disorder with language delay and axial hypotony with psychomotor delay. At birth lupus anticoagulant was present in four (4%), anticardiolipin antibodies (ACL) IgG in 18 (16%), anti-β2 glycoprotein-I (anti-β2GPI) IgG/M in 16 (15%) and three (3%), respectively. ACL IgG and anti-β2GPI disappeared at 6 months in nine (17%) and nine (18%), whereas APL persisted in 10% of children. ACL and anti-β2GPI IgG were correlated with the same mother's antibodies before 6 months of age (p<0.05). Conclusion Despite the presence of APL in children, thrombosis or SLE were not observed. The presence of neurodevelopmental abnormalities seems to be more important in these children, and could justify long-term follow-up.

OBJECTIVES Influenza vaccination in children with rheumatic diseases is often recommended, but not frequently performed. Our aim was to assess the safety and efficacy of annual influenza vaccination in a longitudinal follow-up study of an unselected group of children with juvenile idiopathic arthritis (JIA). METHODS Thirty-one children with stable JIA (10 boys, 21 girls, mean age 11.0 years) receiving various therapies and 14 children in a control group (10 boys, 4 girls, mean age 11.9 years) were vaccinated with the annual influenza vaccine Begrivac® 2008/2009. The children in both groups were followed for adverse events and infections 6 months after vaccination. Autoantibodies production and antibody titers against three vaccine viruses were determined in serial samples taken before, 1 and 6 months after vaccination. RESULTS Eleven (35%) children with JIA and 5 (36%) children in the control group reported short-term adverse events. A JIA flare was observed one month after vaccination in 4 (13%) patients, and in the following five months in 7 (23%) patients. The response to vaccination after one month was significant in the control and study groups as a whole, but not in a subgroup of 4 children receiving anti-TNF-α therapy. After six months, no significant differences in the protective titers against vaccine viruses among the patient and control groups were observed. Changes in the mean values of autoantibodies after vaccination were found only for IgG aCL in the JIA group. CONCLUSIONS No long-term adverse events were reported after influenza vaccination in JIA and control group. Thirty-five percent of children with JIA experienced flare of the disease after vaccination. Protective antibodies against at least 2 vaccine viruses 6 months after vaccination were detected in all patients.

To define inactive disease (ID) and clinical remission (CR) and to delineate variables that can be used to measure ID/CR in childhood‐onset systemic lupus erythematosus (cSLE).

To cite this article:Žitnik SEK, Vesel T, Avčin T, Šilar M, Košnik M, Korošec P. Monitoring honeybee venom immunotherapy in children with the basophil activation test. Pediatr Allergy Immunol 2011 Doi: 10.1111/j.1399‐3038.2011.01233.x

The antiphospholipid antibody syndrome (APS) is a multisystemic autoimmune disease characterized by thromboembolic events, pregnancy morbidity, hematologic, dermatologic, neurologic, and other manifestations in the presence of elevated titers of antiphospholipid antibodies (aPL). Antiphospholipid antibodies are a heterogeneous group of autoantibodies directed against negatively charged phospholipids or phospholipidbinding plasma proteins. The most relevant aPL for identifying patients at risk for immune-mediated thrombosis are anticardiolipin antibodies (aCL), antibodies against b2 glycoprotein I (anti-b2GPI) and lupus anticoagulant (LA). The classification criteria for APS were developed by consensus and designate patients who suffered from vascular thrombosis or pregnancy morbidity associated with the presence of aPL, detected on two or more occasions at least 12 weeks apart (>Table 160.1). These criteria were developed for classification of adult patients with APS and include pregnancy morbidity as a clinical criterion, which is not applicable for the pediatric population. A classification of ‘‘probable APS’’ has been given to patients with aPL that have non-criteria clinical features associated with APS such as livedo reticularis, thrombocytopenia, nephropathy, and neurologic manifestations. Catastrophic antiphospholipid antibody syndrome (CAPS) is a rare, life-threatening variant of APS, characterized by acute microvascular occlusive disease involving at least three organ systems in less than a week. Etiology The cause of APS remains unknown. It may occur as an isolated clinical entity (primary APS) or in association with autoimmune diseases, infections and malignancies. Primary, isolated APS accounts for approximately half of all pediatric patients with APS. The majority of cases associated with underlying autoimmune disease occur in patients with systemic lupus erythematosus (SLE) and lupus-like disease. Preceding or concomitant infections were found in approximately 10% of children with primary APS or APS associated with autoimmune disease. APS associated with malignancies is exceedingly rare in childhood and accounts for less than 1% of all pediatric APS cases. Epidemiology APS is considered the most common acquired hypercoagulation state of autoimmune etiology, and aPL were reported in up to 25% of unselected children with thrombosis. The average age of onset in 121 pediatric APS patients included in an international registry was 10.7 years with the female-to-male ratio 1.2:1. Children of all ethnic background have been affected with APS. Antiphospholipid antibodies can be found in a high percentage of children that do not experience thrombosis. SLE is the autoimmune disease in which aPL occurs in highest percentage, with the reported mean frequencies of 44% for aCL, 40% for anti-b2GPI, and 22% for LA, respectively. The estimated incidence of thromboembolic events in pediatric SLE patients with positive LAwas 54% and with positive aCL 22%. Lowlevels of aPL can be found in childrenwithout any underlying disorder. These naturally occurring aPL are usually transient and could be the result of previous infections or vaccinations that are common in the pediatric population. LA can be rarely found in apparently healthy children as an incidental finding of prolonged activated partial thromboplastin time (aPTT) in pre-operative coagulation screening. The risk of future thrombosis is exceedingly low in otherwise healthy children who were incidentally found to have positive aPL.

In the last decades, the spectrum of primary immunodeficiency diseases (PIDs) has greatly widened, including disorders that can variably impair different immune functions. Although several case series have been published for each disorders, no data is available on how these changes have reflected in the clinical practice of pediatric departments. Aim of the study: Based on the analysis of registry data, we evaluated the distribution of diagnoses among different PID categories, the clinical features and diagnostic investigations at disease onset in two pediatric departments, namely in Slovenia and in Italy. Results: 136 patients have been diagnosed at the two centers, with a widespread distribution into different disease categories. Considering the 109 patients who were still alive at the last follow-up, prevalence of pediatric-onset-PID in our area was roughly estimated to be around 31 per million inhabitants. Diagnosis was genetically confirmed in 79 cases (58.1%), with 29 different genes found mutated. The most common presenting symptoms were: recurrent infections (52.2%), inflammatory manifestations (36.7%), specific syndromic features (30.8%), unusual infections (1.6%) and failure to thrive/growth retardation (22.8%). Treatments at follow-up include antimicrobials (20), hematopoietic stem cell transplantation (17), immunoglobulin replacement therapy (16), and immunosuppressants (9). Conclusions: A huge number of different PIDs are encountered in pediatric departments, often presenting with complex clinical pictures. Our results suggest that the identification of PID may be improved by a multidisciplinary approach, attaching importance not only to infections but also to other symptoms arising from a defective immune function.