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Objectives To describe the disease characteristics, continuous course and long-term outcome and to evaluate predictors of outcome in JIA in Greece. Methods We performed a retrospective cohort analysis of 17 years' prospective data on JIA. Outcome assessment included radiographic (modified Sharp-van der Heidje score), articular and extra-articular damage (Juvenile Arthritis Damage Index), functional ability (HAQ Disability Index), and the cumulative percentage time spent in a state of active disease and also in clinical remission off medication (CR) (according to Wallace's criteria). Results One hundred and two (72 females) patients under regular follow-up were enrolled. The disease age of onset [mean (SD)] was 7.7 (4) years, the interval from onset to last visit was 17.2 (6.7) years and the patients' current age was 25 (5.9) years. At the last follow-up visit, 53 patients (52%) had disease activity, while 23.5% were in CR. The cumulative percentage time spent in a state of active disease and CR over the disease course was 52.6 and 17.8%, respectively. Polyarticular subtype of onset and longer disease activity during the first 5 years were independent predictors of worse outcome. Additional telephone-based interviews of 205 former JIA patients who had been lost to follow-up as adults were performed to extend the interpretation of our findings to a broader JIA population. Almost half (47.6%) of the total cohort of 307 patients were found to be in CR at the final evaluation and 69.7% had no disability. Conclusion The available data indicate that JIA as a whole is a heterogeneous disease with significant variability in course and long-term outcome.

Summary The discovery of serum biomarkers specific for paediatric lupus nephritis (pLN) will facilitate the non-invasive diagnosis, follow-up and more appropriate use of treatment. The aim of this study was to explore the role of serum high-mobility group box 1 (HMGB1) protein, antibodies against nucleosomes (anti-NCS), complement factor C1q (anti-C1q) and glomerular basement membrane (anti-GBM) in pLN. Serum samples of 42 patients with paediatric systemic lupus erythematosus (pSLE) (22 with pLN and 20 without renal involvement), 15 patients with other autoimmune nephritis (AN) and 26 healthy controls (HCs) were examined using enzyme-linked immunosorbent assay (ELISA). The activity of both pSLE and pLN was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) tool. The levels of all four biomarkers were significantly higher in pLN compared to AN and to HCs. The anti-NCS, anti-GBM and HMGB1 serum levels were significantly higher in pLN than in pSLE without renal involvement. The anti-C1q and the HMGB1 serum levels were correlated positively with pSLE activity. The HMGB1 serum levels were also correlated positively with pLN activity. These findings suggest that serum anti-NCS, anti-GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas anti-C1q only of pSLE activity.

Measles outbreaks have surfaced in Europe during the last decades. Infants &lt, 12 months of age were the most severely affected pediatric population. The aim of this study was to investigate the duration of maternally derived measles antibodies in infants aged 1 to 12 months in relation to maternal humoral immune status and other parameters. In a prospective, cross-sectional cohort study, 124 mother/infant pairs and 63 additional infants were recruited from October 2015 through December 2019. Infants were hospitalized in a university pediatric department of a general hospital. Demographic and epidemiological data were recorded and blood samples were collected from mothers and their infants. Commercially available enzyme-linked immunosorbent assay (ELISA) was used for measuring measles antibodies. Fifty nine percent of mothers had vaccine-induced and 15% infection-acquired measles immunity. Eighty-eight percent and 94% of infants were unprotected by 5 and 10 months of age, respectively. Maternal antibody levels and infant age were significant independent predictors of infants’ antibody levels whereas the method of maternal immunity acquisition, age, and origin [Greek/non-Greek] were not. Our findings suggest that about 90% of infants are susceptible to measles beyond the age of 4 months. To our knowledge, these are the first data from Greece reported under the current community composition and epidemiological conditions.

To assess longitudinally the course and outcome of juvenile idiopathic arthritis (JIA) in patients diagnosed and followed-up exclusively in the biologic era; also, to define possible predictors of the disease progression and need for early implementation of biologicals. Prospective and retrospective, monocentric cohort study of 120 JIA patients, diagnosed between 2001 and 2010, and followed-up for ≥ 4 years (median 8.04). Disease activity, cumulative articular/extra-articular damage and quality of life were evaluated by the assessment tools Juvenile Arthritis Disease Activity Score (JADAS71), Juvenile Arthritis Damage Index (JADI) and Childhood Health Assessment Questionnaire (CHAQ), respectively. Moreover, potential predictors of the disease progression and their relation to biologic therapy were investigated. High JADAS71 score (> 9) at diagnosis was indicative of progression to polyarticular course and the need for early introduction of biologic treatment. Other independent predictors of progression to polyarthritis, were: involvement of upper limb, hip and ankle within 6 months following JIA diagnosis and percentage of cumulative time with active disease > 35% within the first year. At the end of the study, both the median JADAS71 score and the Disability Index were significantly lower than the initial (p

The immunomodulatory effects of liposomal amphotericin B (LAMB), amphotericin B lipid complex, and amphotericin B colloidal dispersion (ABCD) on antifungal activity of human monocytes (MNCs), an important component of antifungal host defense, against Aspergillus fumigatus were compared to those of deoxycholate amphotericin B (DAMB). MNCs from healthy volunteers were incubated with 1 or 5 μg/ml DAMB and 5 or 25 μg/ml lipid formulations for 22 h. Drug-pretreated or untreated MNCs were then washed and assayed for the following: (i) activity against A. fumigatus hyphae by XTT assay at MNC:hypha ratios of 10:1 and 20:1; (ii) production of superoxide anion (O 2 − ) from MNCs in response to hyphae by cytochrome c reduction; (iii) production of hydrogen peroxide (H 2 O 2 ) and H 2 O 2 -dependent intracellular intermediates (DIIs), such as OH − and HOCl, from MNCs in response to A. fumigatus culture supernatant by flow cytometric measurement of dihydrorhodamine-1,2,3 oxidation. With the exception of 1 μg/ml DAMB and 5 μg/ml LAMB or ABCD at 10:1, all amphotericin B formulations at both concentrations and MNC:hypha ratios enhanced MNC-induced damage of A. fumigatus hyphae compared to results with untreated cells ( P < 0.01). While MNC O 2 − production upon hyphal challenge, an early event in oxidative burst, was not affected by the drugs, production of H 2 O 2 and DIIs, late events, were significantly increased by all four drugs ( P < 0.01). At clinically relevant concentrations, both conventional amphotericin B and its lipid formulations enhance antihyphal activity of MNCs against A. fumigatus in association with significant augmentation of H 2 O 2 and DIIs but not O 2 − , further demonstrating the immunomodulatory antifungal activities of these agents.

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase, critical for B-cell development and function. Mutations that inactivate this kinase were found in families with X-linked agammaglobulinaemia (XLA). In this study the Btk gene was analyzed in 13 registered Greek patients with XLA phenotype originated from 12 unrelated families, in order to provide a definite diagnosis of the XLA. The structure of Btk was analyzed at the cDNA level using the recently developed method, NIRCA (Non-Isotopic-Rnase-Cleavage-Assay). Alterations were detected in all patients and sequencing analysis confirmed the results and defined six novel XLA-associated Btk mutations (three missense mutations: C337G, L346R, L452P; one nonsense mutation: Y392X, and two frameshift alterations: cl211-1212delA, c1306-1307insA). Having defined the genetic alteration in the affected males of these families, the information was used to design polymerase chain reaction (PCR) primers and the Btk segments containing the mutated sequences were amplified from peripheral blood derived genomic DNA of potential female carriers. The PCR products were directly sequenced and carrier status was determined in 12 out of 16 phenotypically normal females analyzed. This protocol can be used once the nature of the Btk mutation has been defined in one of the affected males and provides a convenient, simple and reliable way to determine the carrier status of other female family members. Molecular genetic analysis constitutes a determinative tool for the definitive diagnosis of XLA and may allow accurate carrier and prenatal diagnosis for genetic counselling. (Less)

The aim of this study was to investigate the association of different groups and subgroups of juvenile chronic arthritis (JCA) with HLA class II (DR, DP, DQ) alleles and/or haplotypes. Groups and subgroups were mainly distinguished on the basis of the type of onset, the course and complications of the disease, and some predefined disease markers according to the criteria proposed by the ILAR Standing Committee (Chile, 1994). On the basis of these criteria the following five JCA groups and their subgroups were included in the study: (1) define systemic onset (n = 25) and systemic progressing to persistent arthritis (n = 14); (2) JCA of oligoarthritis onset (O-JCA, n = 124) and of oligoarthritis onset and course (n = 98), O-JCA of early ( 6 years) onset (EOO-JCA n = 71 and LOO-JCA n = 44), O-JCA with ANA positive (n = 69) or negative (n = 55) and O-JCA progressing to extended arthritis (n = 22); (3) JCA of polyarthritis onset (P-JCA) with rheumatic factor (RF) negative (n = 29), and P-JCA RF negative with antinuclear antibodies (ANA) positive (n = 13) or negative (n = 16); (4) JCA complicated with chronic anterior uveitis (CAU, n = 32); (5) juvenile psoriatic arthritis (n = 20). To assess the HLA allele frequencies in the above 223 Greek children with JCA, these frequencies were compared to those of 98 age-matched and 250 adult controls. The main findings were the following. A common HLA-DRB1* allele was not involved in the JCA groups and subgroups studied; on the other hand, the DQA1*0501 allele was found to be associated with different JCA groups/subgroups (O-JCA, P-JCA RF-negative ANA-positive, JCA with CAU), probably suggesting a closer relationship of this locus with the immunogenetic background of JCA. The DPB1*0201 allele was associated with the development of either EOO-JCA or CAU. Susceptibility to CAU was stronger when the DPB1*0201 was combined with the presence of DRB1*13. Another allele, DQB1*0301, was also associated with O-JCA and CAU. Finally, no specific HLA class II allele was found to be related to the presence of ANA or psoriatic lesions or to the severity of the arthritis. Our findings suggest that the wide clinical and laboratory spectrum of JCA is associated with an immunogenetic background that is linked with HLA alleles of more than one locus. Some of them, such as the DPB1*0201 allele, confer susceptibility to certain clinical onsets and courses or complications of the disease. The rapidly advancing techniques of typing of DNA profiles may lead to more definite conclusions.

The objective of this study was to investigate the effect of treatment with recombinant human granulocyte-colony stimulating factor (rhG-CSF) on the neutrophil count and function of preterm neonates with documented sepsis. For this purpose 62 preterm neonates with proven sepsis and 19 healthy preterm ones were studied. Of the 62 patients, 27 septic neonates had an absolute neutrophil count (ANC)5000/mm3 (group A) and were scheduled not to receive rhG-CSF and 35/62 had an ANC5000/mm3 (n=35) and were randomly assigned either to receive rhG-CSF (group B) or not to receive it (group C). rhG-CSF (10 microg/kg) was administered for 3 consecutive days (0, 1, 2). The ANC, plasma levels of G-CSF (ELISA), neutrophil respiratory burst activity (NRBA) and neutrophil expression of CD11a, CD11b and CD11c (flow cytometry) were measured in all septic neonates on days 0 (onset of sepsis), 1, 3 and 5 and in the healthy neonates once within the first 2 days of life. We found that on day 0, G-CSF levels of all groups of septic neonates were significantly higher than those of the healthy ones. The highest levels were observed in group A. NRBA was diminished only in groups B and C and the expression of CD11a and CD11c was reduced in all groups of septic neonates. Administration of rhG-CSF resulted in a rapid and significant increase in ANC, NRBA and CD11a, CD11b and CD11c expression that persisted throughout the follow up. CONCLUSION; The administration of granulocyte colony stimulating factor to septic neonates significantly increases the absolute granulocyte count and enhances the neutrophil respiratory burst and beta2 integrin expression.

We investigated the simultaneous changes in serum levels of HMGB1 and IFN-α as well as in LAIR-1 expression on plasmatoid dendritic cells (pDCs) of juvenile systemic lupus erythematosus (jSLE) patients in order to explore their involvement in the disease pathogenesis and their correlation with disease activity and other characteristics. In total, 62 blood samples were studied from 26 jSLE patients (18 girls), aged 8–16 years. Twenty healthy subjects (16 girls) of comparable age were included as healthy controls (HCs). Concentrations of serum HMGB1 and IFN-α were assessed by ELISA and LAIR-1 expression on pDCs by five-color flow cytometry. The disease activity index was assessed by SLEDAI and ECLAM scores. It was found that mean serum levels both of HMGB1 and IFN-α were significantly increased in jSLE patients compared to HCs and in jSLE patients with active disease with or without active nephritis compared to those with inactive disease. Mean serum levels of HMGB1 were positively correlated with levels of IFN-α and both were positively correlated with the SLEDAI and ECLAM scores. The expression of LAIR -1 on pDCs of jSLE patients was significantly lower than that of HCs. In conclusion, our findings indicate that serum HMGB1 not only represents a potential marker of disease activity but together with the lack of LAIR-1 inhibitory function may contribute to the sustained inflammatory action of IFN-α in jSLE. In this regard, blocking the action of HMGB1 and its receptors or enhancing the expression/inhibitory function of LAIR-1 on pDCs should be included in future immune interventions for controlling jSLE.

Background JIA-associated uveitis is an important cause of ocular morbidity overtime. Objectives To evaluate the risk factors of uveitis development and describe its characteristics and outcome in a cohort of Greek adult patients with JIA. No relevant Greek data have been published so far. Methods Medical charts were reviewed in terms of gender, current age, ILAR category, age and ANA titer at disease onset. For patients with an established uveitis, the type of uveitis, date of diagnosis, uveitis complications (synechiae, cataract, glaucoma) were also recorded. The final ocular outcome was the Best Corrected Visual Acuity (BCVA) at the last follow up visit and was ranked in 3 levels: a) good visual acuity: BCVA ≥20/40, b) impaired visual acuity: BCVA 20/50–20/100, c) legal blindness: BCVA ≤20/200. Results A total of 102 (72 females) patients were enrolled with a disease age of onset (mean ±SD) 7.7±4 years, a disease course 17.2±6.7 years and patients9 current age 25±5.9 years. The JIA subtypes were systemic (12.7%), oligoarthritis (29.4%), polyarthritis (29.4%, 10.8% RF positive), psoriatic (8.8%), enthesitis-related arthritis (17.6%) and unclassified arthritis (1.9%). Uveitis developed in 11 patients (10.8%), mainly in females (10/11 females, p=0.224). In 90.9% of the patients, uveitis was diagnosed within the first 3.5 years of the disease (mean time 2.2, range 0–13 years). In none of these patients uveitis was diagnosed prior to JIA, while in only one, concurrently. Uveitis was mainly bilateral than unilateral (81.8% vs 18.2%). Patients with oligoarticular type of onset had the highest rate of uveitis (9/30, 30%). Patients with uveitis were significantly younger at onset than those free of uveitis (p Conclusions The majority of adults with JIA-associated uveitis had a good visual bilateral acuity after a -17 year disease onset. ANA positivity and younger age at disease presentation have been proved to be independent risk factors for uveitis development in Greek patients, too. References Saurenmann et al (2007). Arthritis Rheum. 56:647–57. Disclosure of Interest None declared

Background The use of biologic factors in the management of Juvenile Idiopathic Arthritis (JIA) has changed dramatically the course and outcome of the disease. They control the disease symptoms and hinder the joint damage which may provoke major functional limitations, thus affecting the patients’ Health Related Quality of Life (HRQoL). Aim To evaluate changes in the HRQoL variables in patients with JIA, under anti-TNF treatment. Methods 49 patients with refractory to conventional therapy JIA, aged 2-18 years, were studied. They were receiving either Etanercept or Adalimumab for the first time or they were switchers from one anti-TNF to the other one (10/49). All patients were clinically and laboratory assessed pre-treatment and thereafter every 6 months, until the completion of 2 years. At the same timepoints, the following variables were collected: the Childhood Health Assessment Questionnaire (CHAQ) Disability Index (DI), the patient’s/parent’s global assessment of pain and wellbeing (P/PVAS) and the physician’s global assessment (MDVAS) through the visual analogue scale (VAS). Results During anti-TNF treatment, all the above mentioned core set variables P/PVAS showed a significant improvement (p

Results At diagnosis the mean (SD) ages were 12.25(0.27) and 33.93(1.32) yrs, whereas the mean follow-up 6.63 (0.59) and 11.6 (0.7) yrs, for jSLE and aSLE respectively. General features, hepatosplenomegaly, lymphadenopathy and haematology abnormalities were more frequent in jSLE patients (p1=0.001, p2=0.025 and p3

Studies in adults with rheumatoid arthritis reported low serum ghrelin that increased following anti-tumor necrosis factor (TNF) infusion. Data on juvenile idiopathic arthritis (JIA) are lacking. The aim of this pilot study was to explore serum ghrelin levels in patients with JIA and the possible association with anti-TNF treatment, disease activity, and nutritional status. Fifty-two patients with JIA (14/52 on anti-TNF treatment) were studied. Juvenile idiopathic arthritis was inactive in 3 of 14 anti-TNF-treated patients and in 11 of 38 non-anti-TNF-treated patients. The nutritional status, energy intake/requirements, appetite, and fasting serum ghrelin levels were assessed. Ghrelin control values were obtained from 50 individuals with minor illness matched for age, sex, and body mass index. Ghrelin levels in patients with JIA were significantly lower than in controls (P.001, confidence interval [CI] = -101 to -331). Analysis according to anti-TNF treatment and disease activity showed that ghrelin levels were comparable to control values only in 3 patients with anti-TNF-induced remission. Ghrelin in non-anti-TNF-treated patients in remission was low. Multiple regression analysis showed that disease activity (P = .002, CI = -84.16 to -20.01) and anti-TNF treatment (P = .003, CI = -82.51 to -18.33) were significant independent predictors of ghrelin after adjusting for other potential confounders. Ghrelin did not correlate with nutritional status, energy balance, and appetite. Serum ghrelin is low in patients with JIA and is restored to values similar to those in controls following anti-TNF-induced remission. Our study provides evidence that TNF blockade is independently associated with serum ghrelin, which possibly contributes to anti-TNF-induced remission. These preliminary results could form the basis for future research.

To evaluate the safety and efficacy of adalimumab (AD) administration in patients with juvenile idiopathic arthritis (JIA).Twenty-six patients were enrolled from January 2004 to January 2008 in this prospective observational study. Inclusion criteria were either unresponsiveness to disease-modifying anti-rheumatic drugs (DMARDs; n = 17) or to other anti-tumour necrosis factor (anti-TNF) agents (n = 9) or development of uveitis under other anti-TNFs (n = 2 of the 9). Efficacy was estimated using the American College of Rheumatology Pediatric (ACR Pedi) criteria.After 1-5 years of AD exposure, nine different adverse events (AEs) were recorded (12.6 AEs/100 patient-years), mainly mild respiratory tract infections and injection site-related reactions. Serious AEs (SAEs, 2.8/100 patient-years) were the development of abscess at the site of injection (n = 1) and lethal sepsis (n = 1). The ACR Pedi ≥ 30 responses for the first to the fifth year of treatment were 88.5, 57.7, 50.0, 34.6, and 11.5%, respectively. In total, 17 of the 26 (65.4%) patients responded to AD. Five of the 11 patients under steroids discontinued them 6 months post-treatment. Seven patients required weekly AD treatment to maintain remission and four of them benefited from this policy. Recurrent uveitis was hindered in three of the six patients, no new cases were recorded, and radiological regression was observed in two of the four patients with lesions.AD was safe and efficacious during the study period in the majority of patients. However, vigilance is required for the early detection of severe and potentially fatal infections. AD may control recurrent uveitis and radiological progression.

Bronchoalveolar lavage (BAL) is a useful bronchoscopic technique. Studies in "normal" children are limited.To provide data on BAL reference values from Greek children and compare BAL cellular and noncellular components in children with inflammatory and non-inflammatory lung diseases.Seventy two children, aged 2.5 months to 16 years, underwent diagnostic bronchoscopy and BAL. Patients were divided in two groups whether lung inflammation was absent or present. Differential cytology, flow cytometry for lymphocyte subsets and cytokine and chemokine measurements were performed on BAL fluid.Alveolar macrophages were the predominant cellular population in normal children. Patients with inflammatory pneumonopathies had significantly more neutrophils. There was no difference in lymphocyte subpopulations. Values of CD4+/CD8+ ratio in BAL was similar to that reported in adults. Levels of IL-8 and TNF- alpha were significantly higher in children with inflammatory lung diseases.This study provides the first data on BAL of "normal" Greek children. BAL from patients with pulmonary inflammation was characterised by neutrophilia. Finally, we propose that measurement of IL-8 and TNF-a levels in BAL could help in early identification of inflammation in the tracheobronchial tree.

Assessment of the post-etanercept (ET) disease course in patients with juvenile idiopathic arthritis (JIA) who discontinued the drug due to disease remission, using a recently developed tool that scores the disease activity.Eleven patients (F/M 9/2, median age 9.2 years), with either a polyarthritis' (9) or an oligoarthritis' (2) disease course were followed up for 12.25-27 months after ET withdrawal. The median treatment period under ET was 36 months. The Juvenile Arthritis Disease Activity Score (JADAS) was used to grade the JIA activity at the time of ET commencement, at discontinuation and at the time of the flare.All 11 patients flared during the follow-up period. Compared to the time of ET initiation, JADAS was significantly reduced at ET discontinuation as well as at the time of the flare (26.3 to 0 and to 9.5 respectively, p0.001). The median remission following ET discontinuation lasted 3 months. The flares were controlled with methotrexate±cyclosporine A in 10 patients and methotrexate plus anti-TNF in the remaining one.All patients after ET withdrawal flared but they had a minor disease activity score compared to the time of ET initiation. Flares were mostly controlled by the administration of 1 or 2 disease modifying anti-rheumatic drugs. JADAS was found to be a useful and handy tool for assessing and following-up the JIA activity over the disease course.

Our aim was to study the effect of anti-TNF treatment on immunogenicity and safety of the 7-valent conjugate pneumococcal vaccine in children with juvenile idiopathic arthritis. Thirty-one children (mean age:12.9+/-4.6 years) treated with anti-TNFs plus Disease Modifying Anti-Rheumatic Drugs (DMARDs) and 32 age-matched children treated only with DMARDs were vaccinated with two doses of PCV7. After the first vaccine dose geometric mean titers (GMTs) were significantly increased for all vaccine serotypes (p0.0001) in both groups and were found to be protective (0.35microg/ml) in 87-100% of all children, depending on the serotype. Children receiving anti-TNFs achieved a significantly lower GMTs against serotypes 4, 14 and 23F (p0.05). Aor=4-fold increase of the baseline titers toor=5 vaccine serotypes was observed in 50% and 75% of the anti-TNF and control patients, respectively (p=0.0697). No patient developed vaccine-associated serious adverse events or disease flares.

To the Editor: We read with interest the article by Krab et al. We would like to add our experience on the impact of Neurofibromatosis type 1 (NF1) on the Health-Related Quality of Life (HRQoL) of Greek school-aged children. The parents of 43 nonselected children with NF1 (27 boys and 16 girls), ages 6 to 14 years (mean: 10.1 years, SD: 3 years), completed the Child Health Questionnaire–Parent Form 50 (CHQ–PF50) in a prospective observational study. The parental form of CHQ is the only quality-of-life instrument currently translated in Greek, validated, and cross-culturally adapted for use in Greek children. All the children included in the study met the diagnostic criteria of the National Institutes of Health and had been regularly followed from the age of the diagnosis at the Department of Pediatrics of a tertiary care university hospital. The results of the parental reports of the NF1 group were compared with those of a group of 61 healthy aged-matched peers (Table). The comparison between the two groups showed that almost every aspect of the HRQoL of children with NF1 is, according to their parents, significantly affected by their condition. A significant positive correlation has been found between lower CHQ-PF 50 scores and disease complications, especially optic pathway gliomas (P < .05) and cognitive deficits (P < .01). Furthermore, better family relations and stronger family cohesion positively correlated with better physical and psychological adjustment of the children (P < .01). Our results are in accordance with the observations already made in adolescents and children demonstrating that NF1 adversely affects HRQoL of affected children. Diseaserelated and family-related variables seem to influence the outcome of HRQoL measures. Athanasios Vardarinos, MD, PhD Dimitrios I. Zafeiriou, MD, PhD Euthymia Vargiami, MD, PhD Polyxeni Pratsidou-Gertsi, MD, PhD Eleutherios Kontopoulos, MD, PhD Florentia Kanakoudi-Tsakalidou, MD, PhD First Pediatric Department Aristotle University of Thessaloniki

Results Safety: Common respiratory tract infections were recorded in 28% of pts (10/34 under ET and 3/14 under AD). Serious infections were recorded in 4.7% (1 ET, 1 AD). No other serious adverse effects were recorded. Efficacy: ACRped 50–70. 1 st yr: 88% of the ET and 68% of the AD group. 2 nd yr: 81% of the ET and 66.7% of the AD group. 3 yr: 83% of the ET and 100% of the AD group. During the 5-yr period, 11/46 pts (28%) switched from ET to AD or vice versa. Of all patients, 32.5% discontinued anti-TNF treatment due to remission and 52.2% had a satisfactory response (ACRped 50–70), while 8.7% had a poor response either to ET or AD. Conclusion Most of the patients with refractory to conventional treatment JIA respond satisfactorily to the long-term administration of anti-TNFs. The first 2 years are critical to predict a good and sustained response. Although serious infections are rare, a systematic vigilance is warranted in order to avoid fatal outcomes. from 15th Paediatric Rheumatology European Society (PreS) Congress London, UK. 14–17 September 2008

Background The course and outcome of oligo-JIA is more or less unpredictable. So far, no internationally acceptable prognostic biomarkers, regarding the progression of oligo- to the extended disease type have been defined. Objectives The aim of this study was to assess the immunophenotype plus cytokine profile in synovial fluid (SF) of patients (pts) with JIA and to evaluate the findings in respect to the severity of the disease course in order to define those pts who need early aggressive treatment. Methods 73 SF samples from the knees of 57 JIA patients (F: 48, median age 11.49 yrs) were studied. 20/57 pts had oligo-persistent (O-per), 27 oligo-extended (O-ext) and 10 polyarthritis (poly). 25 age-matched children (25 SF samples) with recent traumatic knee arthritis served as controls. The SF immunophenotype and cytokine levels were assessed by flow cytometry and ELISA respectively. Results The median CD4:CD8 T cell ratio was found to be significantly lower in 19/57 pts (24/73 samples) from all 3 JIA pt groups as compared to the controls (0.75 vs 1.55, p Conclusions A low ratio of CD4:CD8 T cells in combination with high levels of IL-17 and IL-23 in SF of JIA pts can predict a prolonged, polyarticular course of the disease and may be used as “the window of opportunity” for a more targeted treatment. References Hunter PJ, et al. Biologic predictors of extension of oligoarticular juvenile idiopathic arthritis as determined from synovial fluid cellular composition and gene expression. Arthritis Rheum 2010;62: 896-907. Disclosure of Interest None declared

To investigate the clinical use patterns, clinical effect and safety of cyclosporine A (CSA) in juvenile idiopathic arthritis (JIA) in the setting of routine clinical care.An open-ended, phase IV post marketing surveillance study was conducted among members of the Pediatric Rheumatology Collaborative Study Group (PRCSG) and of the Paediatric Rheumatology International Trials Organisation (PRINTO) to identify patients with polyarticular course JIA who had received CSA during the course of their disease.A total of 329 patients, half of whom had systemic JIA, were collected in 21 countries. Data were collected during 1240 routine clinic visits. CSA was started at a mean of 5.8 years after disease onset and was given at a mean dose of 3.4 mg/kg/day. The drug was administered in combination with MTX in 61% and along with prednisone in 65% of the patients who were still receiving CSA. Among patients who were still receiving CSA therapy at the last reported visit, remission was documented in 9% of the patients, whereas in 61% of the patients the disease activity was rated as moderate or severe. The most frequent reason for discontinuation of CSA was insufficient therapeutic effect (61% of the patients); only 10% of the patients stopped CSA because of remission. In 17% of the patients, side effects of therapy was given as the primary reason for discontinuation.This survey suggests that CSA may have a less favourable efficacy profile than MTX and etanercept, whereas the frequency of side effects may be similar. The exact place of CSA in the treatment of JIA can only be established via controlled clinical trial.

To study the immunogenicity, safety and efficacy of influenza vaccine in children with chronic rheumatic diseases (CRD) receiving long-term immunosuppressive therapy.Seventy children (F:M 51:19) with CRD (JIA = 49, SLE = 11, other = 10) aged 4-17 yrs and 5 healthy siblings of the patients (aged11 yrs) received a "split type" influenza vaccine (Fluarix SB) licensed for the 1999-2000 winter season. Clinical and laboratory evaluation were performed at study entry and at 1, 3 and 6 months after vaccination. Blood samples were collected before and one month after vaccination and antibody titers to A/Beijing, A/Sydney and B/Beijing influenza antigens were measured using a standardized hemagglutination inhibition assay.Patients were assigned to groups according to the therapeutic regimen [prednisone (PDN), PDN plus 1 disease modifying antirheumatic drug (DMARD), PDN plus 2 DMARDs and 1 or 2 DMARDs without PDN]. 5/70 patients reported local (3) or systemic (2) reactions and 1/5 siblings local reaction. Nine more patients reported mild upper respiratory tract symptoms 1-4 weeks post-vaccination. No patient was found to fulfill criteria for deterioration or flare of the underlying disease. At completion of vaccination 97.14% of patients developed protective HI titers to A/Beijing, 100% to A/Sydney and 80% to B/Beijing. No significant difference in the mean geometric titers was found between patients with different therapeutic regimens or age or between those with JIA or SLE. Disease activity was not related with response or non-response to B/Beijing. No patient reported "flu-like" symptoms during the 6-month period of follow-up.The results of our study indicate that children with CRD receiving long-term immunosuppressive therapy at conventional doses respond to influenza vaccination similarly to healthy children without serious adverse reactions or disease flares regardless of their age, type of CRD or therapeutic regimen.

We report herein the results of the cross-cultural adaptation and validation into the Greek language of the parent's version of 2 health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Greek CHAQ CHQ were fully validated with 3 forward and 3 backward translations. A total of 143 subjects were enrolled: 82 patients with JIA (28% systemic onset, 24% polyarticular onset, 10% extended oligoarticular subtype, and 38% persistent oligoarticular subtype) and 61 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Greek version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

SummaryThe aim of this study was to investigate the effect of prematurity, neonatal sepsis, respiratory distress syndrome (RDS) and perinatal asphyxia on monocyte HLA-DR expression of neonates using a flow cytometric method based on monocyte negative selection. The subjects were one hundred and thirty-one neonates (59 healthy, 44 septicaemic, 20 with RDS and eight with perinatal asphyxia) and 20 healthy adults. Monocyte HLA-DR expression was measured using one-colour HLA-DR labelling in a gate for monocytes obtained using the combination of CD3-CD19–PE/CD15–FITC MoAbs. In addition, the common dual staining method using MoAbs against two CD14 epitopes (TUK4, MO2) was evaluated. With the one-colour HLA-DR labelling higher purity and recovery values of monocytes were achieved than with the dual labelling method. Healthy neonates had significantly lower percentages of HLA-DR+ monocytes than adults (69 ± 13% versus 91·5 ± 2·5%) and comparable mean fluorescence intensity (MFI) (119 ± 25 versus 131 ± 26). Values did not differ significantly between healthy term and preterm neonates. Preterm neonates with RDS had a significantly lower percentage of HLA-DR+ monocytes than the healthy preterm neonates. In neonates with asphyxia both parameters were comparable to those of the healthy ones. Septicaemic neonates presented significantly lower values of both parameters than the healthy, RDS and asphyxiated neonates. Monocyte negative selection provides a reliable estimation of HLA-DR expression on monocytes. Expression of monocyte HLA-DR is lower in healthy neonates in comparison with adults and is further decreased in neonates with sepsis and RDS, but it is not influenced by prematurity and perinatal asphyxia.

8.1 Aseptic femoral necrosis in a patient with systemic JIA {#article-title-2} A 15 year old girl with a systemic onset of JIA and a persistent systemic course, who had been followed up for 14 months in our clinic, presented with a continuous pain, unresponsive to analgesics, located in the soft tissues of the lower part of her right thigh. Up to that time the patient had received prednisone (PS) 0.8→0.3 mg/kg/d for 4 months and then on alternate days, methotrexate 15 mg/m2 and indometacin 2 mg/kg/d. At the time the pain occurred she was receiving indometacin, PS (20 mg/kg/d), and cyclosporin A (3 mg/kg/d). There was no previous history of trauma in the affected limb. Her imaging work up showed the following: x rays of knees and femur—skip lesions in the right femur, one sclerotic in the middle shaft with heavy periosteal reaction and another one mainly lytic with destruction of the cortical bone and periosteal reaction. Magnetic resonance imaging showed skip lesions localised in the middle third of diaphysis and in the distal metaphysis of the femur. The lesions destroyed the cortical bone, infiltrated the bone marrow, and produced a periosteal reaction without extension to the soft tissues or in the epiphysis. These lesions were indicative of a possible bone solid tumour—that is, osteosarcoma or …

The aim of this study was to investigate the association of different groups and subgroups of juvenile chronic arthritis (JCA) with HLA class II (DR, DP, DQ) alleles and/or haplotypes. Groups and subgroups were mainly distinguished on the basis of the type of onset, the course and complications of the disease, and some predefined disease markers according to the criteria proposed by the ILAR Standing Committee (Chile, 1994). On the basis of these criteria the following five JCA groups and their subgroups were included in the study: (1) define systemic onset (n = 25) and systemic progressing to persistent arthritis (n = 14); (2) JCA of oligoarthritis onset (O-JCA, n = 124) and of oligoarthritis onset and course (n = 98), O-JCA of early (6 years) or late (6 years) onset (EOO-JCA n = 71 and LOO-JCA n = 44), O-JCA with ANA positive (n = 69) or negative (n = 55) and O-JCA progressing to extended arthritis (n = 22); (3) JCA of polyarthritis onset (P-JCA) with rheumatic factor (RF) negative (n = 29), and P-JCA RF negative with antinuclear antibodies (ANA) positive (n = 13) or negative (n = 16); (4) JCA complicated with chronic anterior uveitis (CAU, n = 32); (5) juvenile psoriatic arthritis (n = 20). To assess the HLA allele frequencies in the above 223 Greek children with JCA, these frequencies were compared to those of 98 age-matched and 250 adult controls. The main findings were the following. A common HLA-DRB1* allele was not involved in the JCA groups and subgroups studied; on the other hand, the DQA1*0501 allele was found to be associated with different JCA groups/subgroups (O-JCA, P-JCA RF-negative ANA-positive, JCA with CAU), probably suggesting a closer relationship of this locus with the immunogenetic background of JCA. The DPB1*0201 allele was associated with the development of either EOO-JCA or CAU. Susceptibility to CAU was stronger when the DPB1*0201 was combined with the presence of DRB1*13. Another allele, DQB1*0301, was also associated with O-JCA and CAU. Finally, no specific HLA class II allele was found to be related to the presence of ANA or psoriatic lesions or to the severity of the arthritis. Our findings suggest that the wide clinical and laboratory spectrum of JCA is associated with an immunogenetic background that is linked with HLA alleles of more than one locus. Some of them, such as the DPB1*0201 allele, confer susceptibility to certain clinical onsets and courses or complications of the disease. The rapidly advancing techniques of typing of DNA profiles may lead to more definite conclusions.

During a 7 year-period 9 children (7 boys, 2 girls) with juvenile reactive arthritis (JReA) due to Salmonella enteritidis (Se) were prospectively studied because of an unusual type of onset and/or course of the disease. The mean duration of JReA activity was 9 +/- 3.6 months. The mean follow-up time was 55.2 +/- 17.4 months. JReA presented as any of the three types of juvenile chronic arthritis (JCA), namely, as asymmetrical oligoarthritis, polyarthritis, or systemic JCA in 5, 2, and 2 patients respectively. Two patients had pericarditis and three developed the complete or incomplete Reiter's syndrome during the disease or during a recurrence. Five patients carried the HLA-B27 and 3/5 developed psoriatic lesions 1 to 15 months after the onset of JReA. The presence of HLA-B27 and psoriasis was associated with a more prolonged course of JReA. However, no patient developed late radiological lesions or sacroiliitis during follow-up.

Background Nephritis is the most common severe manifestation of pediatric Systemic Lupus Erythematosus (pSLE) and the major predictor of poor prognosis. Research for the detection of novel and accurate biomarkers, predictive of the nephritis outcome, is globally in progress. Ethnicity affects the disease outcome but data on purely Caucasian populations are still limited. Objectives The exploration of the role of serum biomarkers, namely anti-nucleosome antibodies (anti-NCS), anti-C1q antibodies (anti-C1q), anti-glomerular basement membrane antibodies (anti-GBM) and high mobility group box 1 (HMGB1) in pSLE nephritis and the association of their levels with pSLE nephritis and pSLE disease activity. Methods Twenty-four patients (16 female) with pSLE nephritis (44 serum samples, 22 in active nephritis) and 21 patients (18 female) with pSLE without nephritis (32 serum samples, 19 in active pSLE) were enrolled in the study. The disease control group included 17 patients with nephritis of other causality (Henoch-Schonlein purpura nephritis, IgA nephropathy, postinfectious glomerulonephritis, membranous glomerulonephritis), who provided equal serum samples. The SLICC renal activity score was applied for assessing pSLE nephritis disease activity and ECLAM for global pSLE disease activity. The biomarkers’ levels were determined by ELISA. Results The pSLE nephritis patients had significantly higher serum levels of anti-NCS [median: 48.89 (IQR: 31.48-80.81) U/ml versus 12.5 (11.5-27.8) U/ml, p Conclusions In this pure Caucasian Northern Greek pSLE population, high serum anti-GBM levels were found to be associated with the presence of nephritis, but not with the disease activity. Serum anti-GBM, anti-NCS, anti-C1q and HMGB1 may be used to differentiate patients with pSLE nephritis from patients with nephritis of other causality. Furthermore, serum anti-NCS and anti-C1q may be useful for the estimation of pSLE disease activity. References Mok CC. Biomarkers for lupus nephritis: a critical appraisal. J Biomed Biotechnol. 2010;2010:638413. Petri M et al. Systemic lupus international collaborating clinics renal activity/response exercise: development of a renal activity score and renal response index. Arthritis Rheum. 2008 Jun;58(6):1784-8. Disclosure of Interest None Declared

Immunologische Storungen bei behandelten Patienten mit Epilepsie sind seit langem bekannt. In vielen Arbeiten sind die niedrigen Immunglobulin-A-Werte (IgA) nach Hydantoinbehandlung dargestellt. Auserdem wurden Beziehungen zwischen Hydantoin und bosartigem Lymphom festgestellt. Manche Patienten zeigten sogar eine Depression der humoralen und zellularen Immunreaktion. Bekannt ist auch, das nach Hydantoin- oder Carbamazepinbehandlung Lupus erythematodes entstehen kann [5, 6].

Background: Neutropenia is a common manifestation in neonates with intrauterine growth retardation (IUGR) related to preeclampsia and has been associated with decreased neutrophil production. In addition, the increased serum levels of soluble Fas Ligand (sFasL) found in neonates born to mothers with preeclampsia have been associated with increased apoptosis. Neutropenia is uncommon in neonates with isolated IUGR. AIM. To assess neutrophil apoptosis in neonates with IUGR born to normotensive mothers. Material and methods: Neutrophil apoptosis was studied in 19 neonates with IUGR born to mothers without hypertension and 19 gestational age matched, appropriate for gestational age (AGA) neonates during the first 12 hours after birth. Neutrophil apoptosis was evaluated by flow cytometric assessment of neutrophils stained with fluorescein isothiocynate (FICT)-annexin-V, propidium iodide (PI) or expressing the Fas molecule. Results: No significant difference in the percentage of neutrophills stained with FICT-annexin-V (mean7,1%, SD 3,9% vs mean 7,8% SD 2,5%, respectively) or with PI (mean 7,6%, SD 4,3% and mean 7,8%, SD 3,4%, respectively) was found between the IUGR and the AGA neonates. Also the percentage of neutrophills expressing the Fas did not differ significantly between the IUGR (mean 30,2%, SD 11,3%) and AGA neonates (mean 24,8%, SD 9,3%). Conclusion: Neutrophil apoptosis in IUGR neonates of normotensive mothers is not increased compared to AGA neonates. We speculate that neutropenia in IUGR is rather attributed to preeclampsia than intrauterine starvation.

Effect of Cetirizine on Circulating Indicators of Persistent Inflammation and Endothelial Cell Activation in Patients With Sickle Cell Disease

ELEVATED CIRCULATING INDICATORS OF PERSISTENT INFLAMMATION AND ENDOTHELIAL CELL ACTIVATION IN PATIENTS WITH SICKLE CELL DISEASE. 110

Increased proportions of CD10, CD19 and HLA-DR+ cells in bone marrow specimens of children with nonmalignant hematologic conditions have been recently identified. In the last 3 years we have been following up 11 children with hematologic disorders who revealed an abnormal immunophenotypic pattern in their bone marrow specimen. The objective of this study was to evaluate this abnormality in association with the patients' clinical course and development of a B-lineage malignancy. The study population consisted of 11 children aged 4 mo to 13 yrs (mean 4,8 yrs) who had undergone bone marrow diagnostic procedures for haematological disorders: neutropenia (2), thrombocytopenia (8) and Fanconi anemia (1). Bone marrow morphological studies in smears and biopsy samples revealed increased numbers of immature cells(28-60%) in 2/11 patients. Flow cytometry analysis of bone marrow biopsy samples (XL-Coulter) showed in all patients an increased percentage of immature B - cell precursors which expressed the lymphocyte surface markers CD19, CD10 (CALLA) and HLA-DR. Results from the immunophenotyping analysis were expressed as percentage of positive cells. The mean values of CD19+, CD10 and HLA-DR+ cells were 46% (±18,5), 44,5%(±23) and 56,3% (±22) respectively. Patients were treated with the standard protocole treatment according to their diagnosis and were followed up for 6 mo - 3 yrs (mean 2 yrs). Clinical and laboratory evaluation during the follow up time show that 9/11 children have recovered completely and 2/11 are still on treatment for their cytopenia. Nevertheless, none of these children has developed malignant lymphoproliferative disease. These findings indicate that an abnormal immunophenotypic pattern is not always consistent with heamatologic malignancy. However, patients with all these findings must have a long-term follow up in order to reach a definite diagnosis.

Objective Recent data in adult Rheumatoid Arthritis support that the Th17 cell-derived cytokine interleukin 17 (IL-17) in the presence of IL-6 and IL-23 plays a critical role in the pathogenesis of chronic destructive arthritis. Data on synovial fluid (SF) concentrations of IL-17 in JIA pts are sparse. We measured concentrations of the above 3 cytokines and assessed the CD4+CD25highFoxP3+ (Treg) and CD4+CD25lowFoxP3T cell subpopulations in the SF of children with JIA. Findings were correlated with SF sRANKL which expresses the osteoclastic activity in active disease.

Familial Mediterranean Fever (FMF), is the second commonest autoinflammatory disease in pediatric Greek patients (pts) after PFAPA. So far, long-term follow-up case series in Greek FMF pts have not been emerged.