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Objective. Juvenile idiopathic arthritis (JIA) is a heterogeneous disease involving chronic arthritis. The clinical course is characterized by a fluctuating pattern of active and inactive disease. We have described in detail the clinical course in different JIA subtypes during the first 2 years after diagnosis and studied its relationship to disease activity in the following years. Methods. Detailed clinical data on different parameters describing the disease activity in sequential time periods covering the first 2 years after diagnosis were retrieved from the charts of 311 patients with JIA and compared between subtypes. In a cohort of 146 patients, the relation of these different clinical variables to the course of disease in the following 3 years was evaluated. Results. The percentage of time with active disease in the first 2 years differed significantly between subtypes. In all subtypes, a broad spectrum of activity was observed. The time with active disease in the first 2 years was the most significant factor associated with the duration of active disease in the following years. Conclusion. Different percentages of time with active disease have been observed between JIA subtypes in the first 2 years. The cumulative duration of activity varied widely within each subtype. Regarding the prognosis of the individual patient, the clinical course in the first 2 years appears to be predictive of the clinical course in the following years. Patients that have less time with active disease in the first 2 years are not likely to develop an unremitting clinical course later on.

We investigated what it means to patients with juvenile idiopathic arthritis (JIA) to grow up with this disease. A qualitative study was conducted using semi-structured, in-depth interviews of 11 patients with JIA, aged 18-30 years. Interviews were tape recorded and transcribed verbatim. Data were analysed using procedures inherent to the grounded theory approach. Five main themes emerged: physical impact, medication, relationships and family, friends, and perceptions of their future. The physical impact of JIA involved functional limitations, pain, and fatigue. Taking medication properly was difficult; side effects were seen as a problem. With regard to relationships and family, JIA affected the subjects in their roles as family members and affected intimate relationships, pregnancy, and raising children. Indeed, the majority of the patients were afraid to become pregnant or to have children. Most patients found friends who understand their situation and who are a big support. Some patients were afraid of what the future would bring. A better understanding of the psychosocial needs of adolescents with JIA and getting insight into what it means to grow up with this condition will assist healthcare professionals to target interventions that are timely and effective in transitional care to adulthood.

Medical follow-up in the most appropriate treatment setting is important for patients with juvenile idiopathic arthritis (JIA). The aims of this study were 1) to identify the settings in which JIA patients are followed up after leaving paediatric rheumatology, and 2) to compare the clinical profile of patients in different settings.The Short Form-36, Health Assessment Questionnaire, and linear analogue scale for quality of life were sent to JIA patients older than 16 years, who had been followed in one academic paediatric rheumatology centre from 1994 to 2007 and who did not participate in a structured transitional care program. Forty-four patients participated in this cross-sectional, comparative study.Thirteen patients were no longer in medical follow-up, 6 patients were followed by their general practitioner, and 25 patients were followed by a rheumatologist. All patients treated with glucocorticosteroids, DMARDs and anti-TNF were followed by a rheumatologist. Patients under the care of a rheumatologist had worse physical functioning (U=33.5, p0.001); greater disability (U=49.0, p=0.001); more pain (U=59.0, p=0.002); and lower quality of life (U=69, p=0.02) than patients not in follow-up. Of the patients no longer in follow-up, 2 (16.7%) had disabilities and 5 (41.7%) reported persistent pain.The present data indicated that JIA patients with persistent disease and associated functional disabilities tend to remain in the rheumatology circuit. However, the disease of patients leaving specialised rheumatology care is not necessarily controlled. These data may be helpful for organising the proper transfer of patients from paediatric to adult-focused care.

To describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE).Cases of juvenile SLE-associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve.The study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed.Our findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6-year-old girl with the NOD2 E383K gene substitution. Genotype analysis of the patient's family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patient's mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 "Blau mutations."

An 8-year-old boy presented himself with a nontraumatic acute onset of thoracolumbar pain with an antalgic scoliosis. His past medical history did not reveal any infectious disorder. The back pain kept him from sleep and sports. Imaging revealed calcified intervertebral discs from thoracic intervertebral disc 10-11 to lumbar disc 2-3, with compression of the 11th thoracic root. Conservative treatment with analgesia, nonsteroidal anti-inflammatory drugs, and rest reduced the symptoms within a few days. The boy became asymptomatic within 2 weeks. Magnetic resonance imaging changes diminished in 2 months. Intervertebral disc calcification in children is a rare benign disorder which mostly affects the cervical spine. This is the first case, to our knowledge, of symptomatic intervertebral disc calcification involving the lumbar spine up to lumbar disc 2-3.

Contains fulltext : 80713.pdf (Publisher’s version ) (Closed access) BACKGROUND: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause. METHODS: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs. RESULTS: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients. CONCLUSIONS: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA. METHODS: A case-control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped. RESULTS: In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55-0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61-1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62-0.93, P = 7.08 x 10(-3)). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor-negative polyarthritis [P = 0.038]). CONCLUSION: Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.

Although the diagnosis of spondyloenchondrodysplasia (SPENCD) can only be made in the presence of characteristic metaphyseal and vertebral lesions, a recent report has highlighted the pleiotropic manifestations of this disorder which include significant neurological involvement and variable immune dysfunction. Here we present two patients, one of whom was born to consanguineous parents, further illustrating the remarkable clinical spectrum of this disease. Although both patients demonstrated intracranial calcification, they were discordant for the presence of mental retardation, spasticity and white matter abnormalities. And whilst one patient had features consistent with diagnoses of Sjogren syndrome, polymyositis, hypothyroidism and severe scleroderma, the other patient had clinical manifestations and an autoantibody profile of systemic lupus erythematosus. These cases further illustrate the association of SPENCD with immune dysregulation and highlight the differential diagnosis with Aicardi-Goutieres syndrome and other disorders associated with the presence of intracranial calcification. Undoubtedly, identification of the underlying molecular and pathological basis of SPENCD will provide important insights into immune and skeletal regulation.

Infantile-Onset Panniculitis with Systemic Granulomatosis is a recently described clinicopathologic entity, considered part of the spectrum of pediatric granulomatous inflammatory diseases. Through the International Registry of Pediatric Granulomatous Arthritis (PGA), we now identified 5 children with this disorder, all manifesting from very young age panniculitis, fever, hepatosplenomegaly, arthritis, uveitis and acute phase response. Underlying infections, immune deficiency and autoimmune disease, were excluded. No CARD15 or CIAS1 mutations were found. Histologically, the subcutaneous nodules showed a non-vasculitic non-cytophagic lobular panniculits. Giant and epitheloid cell granulomas were found in liver (pt 1, 5), synovium (pt 2), lymph node (pt 3, 5), colon (pt 3), subcutaneous fat (pt 3), dermis and lung (pt 4). Immunohistochemical study of the granulomas revealed the presence of abundant CD68+ macrophages, numerous CD4+ T lymphocytes and few CD8+ cells. TNF stainings were only weakly positive, conversely abundant IL-6 staining was apparent, especially in the corona of lymphocytes. Despite steroid and cyclosporin treatment, the course was progressive in patient 1 with severe lung involvement and death from respiratory insufficiency at age 14. In patients 2, 3, 4 and 5, therapy with anti-TNF MoAbs allowed better disease control. Infantile onset Panniculitis with Systemic Granulomatosis may be a potentially fatal granulomatous disease in children. Although the response to anti-TNF MoAbs in four of our patients is of note, the paucity of TNF with overwhelming presence of IL-6 in situ in granulomas suggest the implication of alternative immune-inflammatory pathways. The role of the Th17 pthway is currently under investigation

Results We identified 169 children treated for refractory AID: autoimmune cytopenia (s) (104 patients), systemic lupus erythematosus (SLE) (52 patients), miscellaneous (13 patients). The mean follow-up period was 6 to 36 months. Patients received 2 to 4 rituximab infusions (350–750 mg/m2) associated with immunosuppressive drugs in 49/ 52 SLE patients. Replacement intravenous immunoglobulins therapy was given to 68/169 patients. Moderate side effects were observed in 50/169 patients: infusion-related reactions, infections, transient neutropenia > 0.5 × 109/L and serum sickness disease. Severe side effects were observed after rituximab infusion in 11/169 (6.6%) patients: severe infusion related hypotention (4 patients), neutropenia < 0.2 × 109/L (3 patients), (2 SLE patients), cerebral vasculitis (1 SLE patient). Two SLE patients who have received cyclophosphamide died from cerebral histoplasmosis and Staphyloccoccus aureus endocarditis, and one boy who underwent autologous bone marrow transplantation for severe thrombocytopenic purpura developed severe enteroviral meningoencephalitis ; Ig G level was low at time of infection in 3/4 patients and not available in the fifth. Conclusion Severe adverse events were recorded in 6.6% of the rituximab-treated children. Patients who have received previous, concurrent and/or subsequent immunosuppressive drugs may experience severe infections, and must be closely monitored. A cohort study of children treated for auto-immune diseases with rituximab has been initiated in France since March 2008 to better assess the tolerance of this therapy. from 15th Paediatric Rheumatology European Society (PreS) Congress London, UK. 14–17 September 2008

Address: 1UO Pediatria II, Istituto Gaslini and Dipartimento di Pediatria, Universita di Genova, Genova, Italy, 2University Medical Center, Utrecht, Utrecht, Italy, 3Hacettepe University Faculty of Medicine, Ankara, Turkey, 4Bambino Gesu Pediatric Hospital, Roma, Italy, 5Centre HospitaloUniversitaire de Bicetre, Le Kremlin Bicetre, France, 6Hopital Necker-Enfants Malades, Paris, France, 7University of Wurzburg, Wurzburg, Germany, 8University of Istanbul, Cerrahpasa Medical Faculty, Istanbul, Turkey, 9Universitair Ziekenhuis Leuven, Leuven, Belgium, 10University College London, London, UK, 11Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 12Department of Paediatrics, Charles University, Prague, Czech Republic, 13Department of Rheumatology University Children's Hospital, Ljubljana, Slovenia and 14Faculty Children's Hospital 1st Department for Children and Adolescents, Kosice, Slovakia * Corresponding author

To determine the physiological impact and health risks for walkers during the Nijmegen (the Netherlands) Four Days Marches in 2007, the largest walking event in the world with more than 45,000 participants.Observational study.66 volunteers were randomly selected and counterbalanced for distance walked and gender in this observational study. Subjects walked 30 km (n = 20; 10 men), 40 km (n = 25; 14 men) or 50 km (n = 21; 10 men) per day, for 4 consecutive days. Core body temperature, fluid intake, changes in body weight, plasma sodium concentrations and energy usage were measured before and after the marches.During this event, ambient temperatures ranged from 11.0 degrees C to a maximum 25.4 degrees C expressed as 'wet bulb globe temperature' (WBGT). Heart rate (+38 beats per minute) and core body temperature (+0.8 degree C) significantly increased in all subjects during each day (about 9 hours walking per day at an average of 4.6 km/h), but hyperthermia was not diagnosed (definition:39.0 degrees C). Average fluid intake varied between 2.6 and 3.3 l/d with a range of 0.3-12 l/d. The relative change in body weight associated with this was -3.1 to +4.3%. Mean plasma sodium concentration decreased from 142.4 to 140.6 mmol/l over each walking day. The plasma sodium correlated negatively with fluid intake (r = -0.32; po.001), change in body weight (r = -0.13; p0.05), and walking time (r = -0.37; p0.001). A high prevalence of hyponatraemia (5%) and hypernatraemia (16%) was observed; extrapolating these findings to the entire field a large group (about 10,000) would have been at risk with this electrolyte imbalance.This study showed that walking the Four Days Marches in Nijmegen with mild ambient conditions led to one in five participants incurring disturbances in fluid and electrolyte balance. Nonetheless, the participants were well able to keep their increasing core temperature within safe limits. Apart from the frequent electrolyte imbalance, the fluid intake varied strongly between individuals.

Open Access Poster presentation Macrophage activation syndrome (MAS) in juvenile systemic lupus erythematosus (JSLE): an underrecognized complication? A Parodi*1, S Davi1, AB Pringe2, S Magni-Manzoni3, P Miettunen4, B BaderMeunier5, G Espada6, S Ozen7, D Wright8, C Magalhaes9, P Woo10, R Kubchandani11, A Grom12, H Michels13, C Wouters14, CE Toro Gutierrez16, G Sterba15, K Hayward17, D Guseinova18, A Fischer19, E Cortis20, M Vivarelli20, A Pistorio1, N Ruperto1, I Sala1, A Martini21 and A Ravelli21

Purpose To investigate the safety and pharmacokinetics (PK) of combined treatment with letrozole and the oral mTOR inhibitor RAD001 in patients with metastatic breast cancer stable or progressing after ⩾4 months on letrozole alone. Methods Eighteen patients received letrozole (2.5 mg/day) and RAD001 at 5 mg/day (cohort 1) or 10 mg/day (cohort 2). In the absence of DLT in cohort 1, cohort 2 was expanded to 12 patients to obtain additional safety and PK data. Results Most common adverse events were stomatitis (50.0% of patients), fatigue (44.4%), anorexia and/or decreased appetite (44.4%), diarrhoea (38.9%), headache (33.3%) and rash (33.3%). There was 1 DLT, a grade 3 thrombocytopaenia in cohort 2. No clinically relevant PK interaction was detected. Seven patients received the combination therapy for >6 months. One patient had a complete response, and one had a 28% reduction in liver metastases, both in cohort 2. Conclusion Daily therapy with RAD001 plus letrozole is promising: the results suggest anti-tumour activity with no PK interactions. The overall safety profile of the combination is consistent with that expected for RAD001 monotherapy. A daily dose of RAD001 10 mg is recommended for further trials.

To perform a prospective, comprehensive, clinical, and radiological evaluation of temporomandibular joint (TMJ) involvement and its influence on craniofacial growth, in a cohort of patients with juvenile idiopathic arthritis (JIA), representing all JIA subtypes.Clinical rheumatologic and orthodontic evaluations were performed in 100 patients with JIA [12 systemic arthritis, 24 rheumatoid factor (RF)-negative polyarthritis, 1 RF-positive polyarthritis, 39 oligoarthritis, 22 enthesitis-related arthritis, 2 psoriatic arthritis]. An orthopantomogram and lateral cephalogram were performed in 46 patients. The prevalence of TMJ arthritis was studied in relation to JIA subtype and disease characteristics; cephalometric measurements were compared to those from age- and sex-matched healthy controls.Whereas 55% of patients with JIA had at least one symptom/sign of TMJ arthritis, 78% of the radiographed group exhibited condylar lesions. The presence of condylar damage was not related to clinical orthodontic findings or to JIA subtype, disease activity, severity, or duration. Patients with JIA exhibited larger mandibular plane and A-nasion-B angles, larger total anterior facial height, smaller interincisal and sella-nasion-B angles, and shorter mandibular ramus lengths than their age- and sex-matched controls. Craniofacial alterations were clearly related to the presence of condylar damage, even when present at a minimal degree.Our data show that TMJ condylar damage occurs very frequently in JIA, and irrespective of JIA subtype; condylar lesions can present early, progress insidiously, and -- even at a minimal degree -- can severely alter the craniofacial profile. We propose that the followup of patients with JIA should include early and regular evaluation by an orthodontist, supplemented with radiographic TMJ imaging.

Several studies have reported favorable effects of intravenous immunoglobulins (IVIG) in refractory epilepsy. Evidence substantiating an immunomodulatory action is scarce. In an open-label study, we prospectively investigated the effect of IVIG on clinical, EEG and serum/CSF immunological parameters in patients with refractory childhood-onset epilepsy.Thirteen patients (median age 6.9 years; range 1.6-25.8) with refractory seizures despite 3-4 antiepileptic drug regimens were given IVIG (Sandoglobulin, ZLB-Behring, add-on, 4 x 400 mg/kg/3 weeks). Seizure frequency, 24-h video-EEG, and CSF/serum immunological parameters and cytokine profiles (IL-6/IL-8/IL-12/IL-10) were documented before and after completion of the course.Seizure frequency was reduced byor = 50% in four, and by 25%-50% in three patients. In contrast, variation in automatically recorded spike counts (1-h-wake and -sleep) did not correlate with clinical improvement. Serum immunological parameters showed variable deviations in eight patients (e.g., IgG(2) deficiency) and CSF immunoblotting showed oligoclonal bands in two patients. Blood-brain barrier permeability was normal in 12 patients. IL-6 and IL-8 were clearly detectable in CSF of all patients; the levels were significantly higher than those in plasma but remained unaffected by IVIG treatment.Despite unchanged EEG spike counts, substantial reductions in seizure frequency occurred in 7 of 13 patients, suggesting that IVIG hinder progression of central epileptic activity into clinical seizures. Intrathecal presence of IL-8 and IL-6 was documented in all patients, but was unaffected by IVIG, suggesting that their production is directly related to electrical seizure activity and that IVIG may act through interference with immune pathways downstream to IL-6 and IL-8.

We report four children with infantile onset lobular panniculitis, high fever, uveitis, and systemic granulomatous inflammation, recruited through the International Registry of Pediatric Granulomatous Arthritis (PGA)-. Neither CARD15 nor CIAS1 mutations were found. Despite immunosuppressive therapy, disease course was progressive. Response to anti-tumor necrosis factor (TNF) monoclonal antibody in 3 patients is of note.

Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. They are defined immunohistologically as KIT positive tumours. The only effective treatment for malignant GIST was surgery until 2000. Imatinib mesylate (STI571, Glivec) has shown substantial anticancer activity in patients with metastatic or unresectable GIST.57 patients who were diagnosed with unresectable or metastatic malignant GIST were entered into this study. The patients were given 400 mg Glivec orally once daily. The dose could be increased to 600 mg orally once daily and then to 400 mg twice daily if tumour progression was noticed. Daily treatment was interrupted or dose was decreased only in the case of limiting toxicities. We evaluated the tumour response and the safety of the drug.85% of GIST patients showed a partial response or stable disease after 8 weeks of treatment with imatinib. The main side effects were nausea, vomiting, anorexia, skin rash, periorbital oedema and diarrhea.This study confirms that imatinib is an active agent against malignant GIST with manageable toxicities.

A high prevalence of low bone mineralization is documented in adult patients with cystic fibrosis (CF). Osteopenia is present in as much as 85% of adult patients and osteoporosis in 13 to 57% of them. In children, studies are discordant probably because of different control database. Denutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity are well known risk factors for poor bone health. Puberty is a critical period and requires a careful follow-up for an optimal bone peak mass. This review is a consensus statement established by the national working group of the French Federation of CF Centers to develop practice guidelines for optimizing bone health in patients with CF. Recommendations for screening and for calcium, vitamin D and K supplementation are given. Further work is needed to define indications for treatment with biphosphonates and anabolic agents.

Publisher Summary This chapter discusses the epidemiology, etiology, clinical manifestations, diagnostic investigations, treatment, and prognosis of childhood sarcoidosis. It is used to designate a chronic inflammatory disease characterized by granulomatous polyarthritis and tenosynovitis, uveitis, and rash. Childhood sarcoidosis is seen typically in children younger than five years of age and is associated with a paucity of constitutional symptoms, namely fever, lymphadenopathy, and fatigue. Pediatric granulomatous arthritis (PGA) is highly associated with mutations in the nucleotide-binding oligomerization domain (NOD) domain Caspase Recruitment Domain 15 (CARD15), a protein involved in inflammation and apoptosis. Both the classical clinical symptom triad of PGA and the association with a genetic mutation in CARD15 are major distinguishing features with adult sarcoidosis. Although with time, expansion of granulomatous inflammation to other disease organs is described, the major causes of morbidity for patients with PGA is progressive polyarthritis and sight-threatening uveitis. For the pathogenesis of PGA, biologic treatments directed at the inhibition of pro-inflammatory cytokines (TNF and IL-1) are used.

Objective. To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA). Methods. This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received MTX plus infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44. Results. Although a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), the between-group difference in this primary efficacy end point was not statistically significant (P = 0.12). By week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients. Infliximab was generally well tolerated, but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose. Conclusion. While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab-treated and placebo-treated patients. Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA. © 2007, American College of Rheumatology.

From 8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases Dresden, Germany. 30 September - 3 October 2015

Background Childhood-onset panniculitides are rare and classically include infectious, connective tissue, malignant, metabolic, and drugs, cold or trauma-induced panniculitis. Some specific types of panniculitis are only seen in neonates and very young infants, and include subcutaneous fat of the newborn, poststeroid panniculitis, sclerema neonatorum, and cold panniculitis. However, no specific discoverable etiology can be identified in many patients. Objectives To describe the spectrum of clinical and pathological manifestations of childhood-onset panniculitis of unknown cause Methods A retrospective single-center study of children presenting with panniculitis diagnosed by skin biopsy Results Eighteen patients were identified. The onset of symptoms occurred within the first two years of life in 15/18 patients (83%). Panniculitis was the revealing manifestation in 15/18 (83%) patients, and relapsed in 13/18 (72%) patients. Associated-non-cutaneous features occurred in 16/18 (89%) patients, especially autoinflammatory manifestations in 13/18 patients (72%), associated with immunodeficiency in 5 patients (low T or B cells count with hypogammaglobulinemia in 4 and 1 patients respectively). Autoinflammatory manifestations consisted in attacks of fever with an elevation of acute phase reactants associated with polyarthritis or polyarthralgia (2 patients), rash (2 patients) or aseptic adenitis (2 patients). Panniculitis was mostly lobular in 10 (55%) patients, septal in 3 (17%) patients or both in 5 patients (28%). Predominant infiltrate consisted of neutrophils, cytophagic histiocytes, lymphocytes, eosinophils in 8 (44%), 5 (28%), 3 (17%), and 1 (5.5%) patients respectively, and included granuloma in 1 patient. No relationship was found between clinical and pathological features. Genomic mutations were identified in 3 of the 4 patients who underwent genetic analysis: mutations in TRNT1, MVK (mevalonate kinase) and LCK genes. Conclusions This series underlines that auto-inflammatory diseases, possibly associated with inherited immunodeficiency, are a main cause of early-onset panniculitis. The identification of a monogenic cause in 3 patients and the early-onset presentation of the disease suggest that a subset of patients has a genetic predisposition to develop panniculitis, especially early-onset panniculitis. Disclosure of Interest None declared

Objective Blau syndrome and its sporadic counterpart, early-onset sarcoidosis, share an identical phenotype featuring the classic triad of arthritis, dermatitis, and uveitis and are associated with mutations of CARD15 in 50–90% of cases. We chose the term “pediatric granulomatous arthritis” to refer to both. An international registry was established in the spring of 2005 to define the phenotype spectrum and establish the mutation frequency and variants. Methods Histologically confirmed granuloma and arthritis were required for inclusion. Probands and relatives were genotyped for CARD15. Deidentified clinical information was collected. Results One year after the inception of the registry, 61 individuals from 22 pedigrees had been entered. Seven pedigrees with 19 individuals (8 affected, 11 unaffected) had clinical disease that was atypical, and none of the individuals in those pedigrees showed mutations. There were 9 classic simplex pediatric granulomatous arthritis pedigrees including 19 individuals (9 affected, 10 unaffected) and 6 classic multiplex pedigrees with 22 individuals (17 affected, 5 unaffected). Cutaneous presentation was the most common. Arthritis was polyarticular in 96% of patients. Isolated eye disease was never the presenting symptom, but significant/severe visual impairment was observed in 41% of patients. Eye disease was bilateral in 21 of 22 patients and was complicated by glaucoma in 6 of 22 patients and by cataracts in 50% of patients. Skin biopsy was the best diagnostic approach (because of accuracy and low invasiveness). Conclusion In this series, the first combining familial and sporadic pedigrees and, to our knowledge, the largest, we further defined the phenotype and showed that all affected classic (and no nonclassic) pedigrees carry a mutation and that there is no asymptomatic carriage. If these data are confirmed, mutation analysis rather than tissue sampling may prove to be the most efficient diagnostic procedure.

To determine the incidence and characteristics of uveitis in a cohort of patients with juvenile idiopathic arthritis (JIA) as well as the nature of treatment and the risk factors for visual loss.Retrospective review of 52 patients with JIA, screened for uveitis between 1995 and 2005. The first group, presenting with symptoms of arthritis and uveitis, was diagnosed at screening. The second group presented with symptoms of uveitis, without any rheumatological complaints at the time of diagnosis. During follow-up, reactivation of uveitis and complications were registered and treated when indicated.Seventeen patients had symptoms of uveitis at time of presentation or developed uveitis at follow-up. Ten of this patient group had oligo-arthritis, 16 were antinuclear antibody (ANA) positive, 16 were girls. Three patients presented with ophthalmological symptoms without rheumatological complaints. In this group, complications were more pronounced. Treatment in all patients consisted of topical corticosteroids and dilating drops at different intervals. Visual acuity was good in most patients.In this retrospective study, the risk of uveitis was higher in ANA- positive girls with oligoarthritis. To reduce severe disease at presentation, earlier diagnosis of JIA, earlier referral for slit lamp examination and universal screening of vision in childhood are necessary.

Congenital diaphragmatic hernia (CDH) is a relatively common birth defect with a high mortality. Although little is known about its etiology, there is increasing evidence for a strong genetic contribution. Both numerical and structural chromosomal abnormalities have been described in patients with CDH. Partial trisomy 11q and partial trisomy 22 associated with the common t(11;22) has been reported in several cases of CDH. It has been assumed that the diaphragmatic defect seen in these individuals was primarily due to duplication of material from chromosome 22q11. However, in this report we describe a family with a t(11;12) in which one of two brothers with partial trisomy 11q has a left sided posterolateral CDH. This is the second case of CDH in partial trisomy 11q due to an unbalanced translocation other than t(11;22). Using array-based comparative genomic hybridization and fluorescent in situ hybridization, we mapped the breakpoints in both brothers and their mother who is a balanced translocation carrier. Our results suggest that duplication of one or more genes on a approximately 19 Mb region of 11q23.3-qter predisposes to the development of CDH. These effects may be the primary cause of CDH in individuals t(11;22) or may be additive to effects from the duplication of chromosome 22 material. We also conclude that the partial trisomy 11q syndrome has a variable phenotype and that CDH should be added to the spectrum of anomalies that can be present in this syndrome.

Acute retinal necrosis (ARN) is a severe ocular syndrome consisting of a moderate-to-severe anterior uveitis, vasculitis, and vaso-occlusive retinal necrosis. It can occur in healthy individuals at any age, but reports of this condition in children are rare.

Pars planitis is the idiopathic form of intermediate uveitis; it most commonly affects persons between 5 and 40 years of age. In childhood, the disease is largely asymptomatic until in a well advanced stage with markedly reduced vision. Lack of early diagnosis and treatment may lead to permanent visual loss and amblyopia.To report on the clinical symptoms, complications, treatment and visual outcome of pars planitis in childhood.Ten patients (8 boys and 2 girls) all younger than 16 years were diagnosed with and treated for pars planitis at our clinic between January 1993 and August 2004.

We report a new case of pediatric carpal tunnel syndrome in a patient with juvenile rheumatoid arthritis. Symptoms were mainly motor weakness and severe atrophy of the thenar.

Congenital diaphragmatic hernia (CDH) has an incidence of 1 in 3,000 births and a high mortality rate (33%-58%). Multifactorial inheritance, teratogenic agents, and genetic abnormalities have all been suggested as possible etiologic factors. To define candidate regions for CDH, we analyzed cytogenetic data collected on 200 CDH cases, of which 7% and 5% showed numerical and structural abnormalities, respectively. This study focused on the most frequent structural anomaly found: a deletion on chromosome 15q. We analyzed material from three of our patients and from four previously published patients with CDH and a 15q deletion. By using array-based comparative genomic hybridization and fluorescent in situ hybridization to determine the boundaries of the deletions and by including data from two individuals with terminal 15q deletions but without CDH, we were able to exclude a substantial portion of the telomeric region from the genetic etiology of this disorder. Moreover, one patient with CDH harbored a small interstitial deletion. Together, these findings allowed us to define a minimal deletion region of similar to 5 Mb at chromosome 15q26.1-26.2. The region contains four known genes, of which two-NR2F2 and CHD2-are particularly intriguing gene candidates for CDH.

The concept that the immune system plays a role in the epileptogenic process of some epileptic syndromes was first proposed more than 20 years ago. Since then, numerous studies have reported on the existence of a variety of immunological alterations in epileptic patients, on the observation of favourable responses of refractory epilepsy syndromes to immunomodulatory treatment, and on the association of certain well-known immune-mediated disease states with epilepsy. This review comprehensively recapitulates the currently available evidence supporting or arguing against the possible involvement of the immune system in the pathogenesis of certain types of epilepsy. It is concluded that an abundance of facts is in support of this concept and that further studies should be directed at substantiating the pathogenic significance of (auto)immune responses in certain types of epilepsy. Current progress in the functional and molecular immunological research techniques will indisputably contribute to the elucidation of this link.

We present a 7-week-old male infant with pseudoscleroderma as a primary manifestation of the Hutchinson-Gilford syndrome of premature aging. He had suffered intra-uterine growth retardation; micrognathism and a cleft palate were evident at birth. He presented with feeding difficulties and severe, diffuse scleroderma-like lesions, a faint peri-oral cyanosis and prominent scalp veins. With time, special facial features became more and more apparent: frontal bossing, prominent eyes, thin and fine nose and lips, microstomia, low-set ears and occipito-parietal alopecia. Histopathology of the skin showed an increased density and thickness of collagen in the dermis and hypodermis. Within the 1st year of life, typical skeletal characteristics were observed. The diagnosis of Hutchinson-Gilford syndrome was confirmed by analysis of the lamin A gene, revealing a heterozygous c.1824C>T (G608G) mutation. Conclusion:Hutchinson-Gilford syndrome is an extremely rare disorder of which the full clinical spectrum becomes evident with time. Sclerodermatous changes in the infant can be the first manifestation.

UNLABELLED The medical literature on early childhood masturbation is sparse. Only 12 patients who presented with infantile self-stimulation under the age of 1 y are described. During the last 2 y, five girls under 1 y of age presented at our department with self-stimulating behaviour. The diagnosis of this behaviour was difficult, but could be made by watching a video of the attacks. Infantile self-stimulation is often misdiagnosed and unnecessary investigations and useless treatments are often prescribed. Video recording can be of great help to put forward the correct diagnosis. Masturbation is not so uncommon and treatment consists mostly in reassuring the parents. It can, however, be associated with behavioural problems. Few data are available on the clinical outcome of childhood masturbation, but most children seem to develop normally. CONCLUSION Infantile self-stimulation should always be considered in the differential diagnosis of "strange episodes or attacks".

Rhabdomyolysis is a potentially lethal disorder, characterized by elevated serum concentrations of creatine kinase (CK) due to skeletal muscle injury. In this paper a patient with diabetic ketoacidosis (DKA) is reported who developed rhabdomyolysis (maximum CK level, 37,700 U/L; normal, < 170 U/L), anemia (6.2 g/dL) and thrombocytopenia (16,000/microL). This combination of rhabdomyolysis with anemia and thrombocytopenia has not yet been reported in DKA. The pathogenic mechanism leading to rhabdomyolysis in DKA remains unsettled. From the literature it seems that those patients who develop rhabdomyolysis have very high glucose levels and a high osmolality on admission. Low phosphate levels can play a role as well. The etiology of anemia and thrombocytopenia in our patient remains obscure. Intravascular hemolysis could not be demonstrated but intramedullar hemolysis, due to osmolar shift or hypophosphatemia, cannot be excluded. A review of the literature data revealed that rhabdomyolysis is not so uncommon in DKA. However, to obtain incidence data in children, prospective studies are necessary.

Tuberous sclerosis complex (TSC) is a genetic disorder characterised by hamartomatous growth abnormalities in many organs. Epilepsy and mental retardation, typical skin manifestations, intracerebral hamartoma, renal angiomyolipoma, and pulmonary lymphangioleiomyomatosis are among the major diagnostic features of TSC.1 TSC is thought to affect approximately 1 in every 6000 newborns. It has an autosomal dominant inheritance pattern, but an estimated 60% of all cases involve new mutations. TSC exhibits locus heterogeneity with two identified genes, one on 9q34 ( TSC1 ) and the other on 16p13 ( TSC2 ).2 The TSC2 gene lies immediately adjacent to PKD1 , the major gene causing autosomal dominant polycystic kidney disease (ADPKD). Both genes are in a tail to tail orientation only 60 bp apart. In 1994, a “contiguous gene syndrome” was described, involving large deletions disrupting both the TSC2 gene and the PKD1 gene.3 Although, overall, 25% to 32% of patients with TSC show some degree of renal cyst formation,4,5 the six cases described in the first report all presented during early childhood with markedly enlarged polycystic kidneys.3 Later reports of the PKD1 - TSC2 contiguous gene syndrome further supported the notion that this disorder is typically associated with severe juvenile polycystic kidney disease.6–8 A systematic mutational analysis of 27 unrelated patients with TSC and multiple bilateral renal cysts showed that 22 had contiguous deletions of TSC2 and PKD1. In 17 patients with constitutional deletions, the median age of presentation was six months (range 1 month to 10 years), with 83% of patients presenting with abdominal masses or distension owing to large cysts. Renal cystic disease was comparatively mild in the patients without the contiguous gene syndrome.7 Here, we present a case of a patient with an exceptionally large, de novo, germline deletion involving the entire TSC2 and …

To determine the immunophenotypic profiles of circulating lymphocytes in patients with different disease types of Juvenile Idiopathic Arthritis (JIA).Peripheral blood lymphocyte subsets from 19 patients with oligoarticular JIA (o-JIA), 10 patients with polyarticular JIA (p-JIA), 12 patients with systemic JIA (s-JlA) andfrom 41 age-matched healthy controls were characterized by two color immunofluorescence flow cytometry analysis.Patients with o-JIA and p-JIA had increased numbers of HLA-DR+ Tcells and Tcells co-expressing CD57 and CD16/56, indicating T cell activation and terminal differentiation of CD8+ T cells respectively. By contrast, in patients with s-JIA there was no increase in the activation or differentiation markers on T cells, but a profound decrease in circulating NK cells. All patients had hypergammaglobulinemia consistent with B cell hyperactivity, but increased numbers of CD5+ B cells were found only in o-JIA and p-JIA.Distinct immunophenotypic lymphocyte profiles in patients with o-JIA and p-JIA compared to patients with s-JIA as demonstrated in this study, are consistent with afundamental heterogeneity of the disease.

Dear Sirs,We read with great interest the article by Jung SK et al. onmesangial proliferative glomerulonephritis and IgA depos-its in a child with Sjogren's syndrome (SS) recentlypublished in Pediatric Nephrology[1]. The most commonform of renal involvement in SS is tubulointerstitialnephritis, generally causing mild renal dysfunction [2].Glomerulonephritis (GN) is rare with membranoprolifer-ative and membranous nephropathy being the mostcommonly described glomerular lesions, whereas cres-centic GN has been only occasionally reported in adults[3, 4]. Wefolloweda12-year-oldgirlwithprimarySS,whopresented with acute renal failure due to pauci-immunecrescentic GN with severe tubulointerstitial damage. Thepatient had a 7-year history of sicca syndrome withenlargement of both lacrimal glands and an abnormalSchirmer's test, pointing to the diagnosis of SS. At theage of 12 years, she presented with general malaise andthe biochemical signs of acute renal failure (creatinine9.5 mg/dl, BUN 103 mg/dl), oliguria (0.4 ml/kg/h),moderate proteinuria (1.23 g/l) and microscopic hematu-ria. Antistreptolysin O, anti-cardiolipin and lupus antico-agulant antibodies were absent. Viral serology (hepatitis Band C, HIV) was negative as well. Rheumatoid factor andC3, C4 complement levels were normal. Anti-DNAantibody titer measured by ELISA was 1:200. ANCA,ANA, and Anti-Ro/SS-A could be measured by immuno-fluorescence on the 90th day only. C-ANCA and p-ANCAwere negative, ANA titer (Hep-2) was 1:160 and Anti-Ro/SS-A were present (+).Renal biopsy contained 54 glomeruli, from which twowere completely sclerotic, four demonstrated fibrocellu-lar crescents, and all remaining glomeruli showed largecellular crescents (Fig. 1a). Tubulointerstitial inflamma-tion with patchy cellular infiltrates containing lympho-cytes, plasma cells, and monocytes was present (Fig.1b).Immunofluorescence with antibodies against IgG, IgA,IgM, C1q, C3, fibrinogen, κ and 1 light chains wasnegative.The patient received three pulses of methylprednisolone1,000 mg daily, followed by oral prednisolone 60 mg/day.Alternate-day plasmapheresis with substitution of 1 plasmavolume (x 4 times) and intravenous cyclophosphamidetreatment (750 mg/m

Mevalonate kinase deficiency (MKD) is a rare hereditary autoinflammatory syndrome that can lead to significant morbidity. Evidence-based guidelines are lacking and management is mostly based on physician’s experience. Consequently, treatment regimens differ throughout Europe. In 2012, a European initiative called SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) was launched to optimize and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases.

Biologic treatments have been introduced for Juvenile Idiopathic Arthritis (JIA) treatment in 2000, and have substantially improved the global prognosis of all disease subtypes. However not all patients respond to one biologic and therapeutic effect of one drug may decrease with time.

Background/Purpose: Dry synovitis is considered to be a rare form of JIA, incompletely understood and following a potentially destructive course. Since its first description only a few reports mention this entity within the spectrum of JIA. We aimed to describe the clinical and radiological manifestations, and the course of dry synovitis and to compare it with classical RF negative polyarticular JIA. Methods: A retrospective study of 10 patients in 3 pediatric rheumatology centers who presented with 1. progressive, symmetric polyarticular stiffness with limitations and without clinical synovitis, 2. radiologic signs of articular damage and 3. Absence of inflammatory parameters (CRP, ESR). Neuromuscular conditions and metabolic storage/bone disorders were excluded. This cohort was compared with 35 consecutive patients with classical polyarticular RF negative JIA. Clinical, laboratory and imaging (X-rays, MRI) data of both groups were reviewed. Results: The dry synovitis cohort included 4 boys and 6 girls. The median (range) age at first manifestation and diagnosis were respectively 4.3 yrs (1.1–8.9) and 7.3 yrs (2.8–14). Presenting signs comprised delayed motor development and/or progressive articular stiffness. Pain complaints emerged with time. Clinical examination showed a symmetric polyarticular involvement without clinical signs of synovitis. CRP was normal and ESR < 8mm/h. In 9/10 patients ANA were absent. Radiological imaging (wrist, ankles and/or pelvis) showed osteopenia, advanced bone age, cartilage loss and/or bone erosions in all patients. MRI revealed synovial thickening in 9/10 patients; bone edema was variably present and bone erosions were demonstrated in 8/10 patients. Treatments comprised NSAIDs (n = 8/10), corticosteroids (n = 8/10), methotrexate (n = 9/10), anti-TNF (n = 6/10), IL-1 receptor antagonist (n = 1/10) and resulted in some subjective improvement. However articular limitations persisted and imaging showed progressive (osteo)articular damage. The comparison of the dry synovitis with polyarticular JIA patients showed that the age at disease onset was comparable in the 2 groups. Significant differential features found in the dry synovitis cohort were higher diagnostic delay, increased number of joint involvement and contractures, lack of swelling and tenderness, and lack of increased acute phase response (CRP, ESR) and ANA. Conclusion: From our data, we conclude that ‘dry synovitis’ can be considered as a clinical descriptive term referring to the development of progressive symmetric polyarticular limitations. We show that MRI is usefull in demonstrating underlying subclinical inflammation and in combination with clinical features and standard X-rays helpful in the differential diagnosis with mucopolyssaccharidosis, neuromuscular disorders and bone dysplasia. Clinical as well as radiological evolution seem to be refractory to the current JIA therapy and to be different among patients diagnosed with ‘dry synovitis,’ suggesting that this clinical manifestation may represent a heterogeneous spectrum of joint and/or bone disorders. The exact nature of this entity and a possible contribution of a metabolic or intrinsic bone disorder into its pathogenesis remain to be determined.

Background/Purpose: CRMO is an autoinflammatory bone disorder, characterized by aseptic multifocal osteitis. MRI is classically used in measuring the extent and activity of the bone lesions and possible soft tissue involvement. Additionally, MRI may be essential to exclude other causes of osteoarticular inflammation. We want to demonstrate the usefulness of MRI in the differential diagnosis of recurrent bone pain with inflammation in children. Methods: evaluation of 2 patients with osteoarticular pain and inflammation. Results: Two patients were referred to our pediatric rheumatology outpatient clinic with the presumed diagnosis of CRMO. Since several months, they experienced episodes of articular pain and joint swelling (patient 1) and recurrent back pain and fatigue (patient 2). In the first patient initial blood evaluation showed mildly increased inflammatory parameters (CRP 75 mg/L) with a mild microcytic anemia (Hb 11 g/dL) and thrombocytosis (557×10e6/μl) with a normal leukocyte count. Conventional X-ray showed no abnormalities. MRI confirmed arthritis/synovitis of both ankles with presence of bone edema in ankle and tarsal bones. Initial treatment with NSAIDs was successful. In patient 2 additional investigations showed also increased inflammatory parameters (CRP 136 mg/L) with a mild anemia, slightly increased thrombocytosis and normal leukocyte count. Initial MRI showed mildly intense signaling of different vertebrae on STIR images. Bone scintigraphy demonstrated multifocal hypercaptation at the right skull, coracoied bone and multiple vertebrae. Additional bone marrow puncture was normal. NSAIDs were started systematically with success. In patient 1, pain returned. PET-CT showed increased metabolism at multiple skeleton foci. Additional bone marrow puncture in the posterior iliac crest returned normal with no arguments for a lymphoproliferative disorder. Persistent and worsening of clinical symptoms prompted us to perform total body MRI which showed multiple, symmetric T1-hypointens signals in the peripheral bones (lower legs, underarms, feet, knees and elbows). Guided by these findings, a targeted bone marrow puncture was performed in the tibia which showed a malignant lymphoproliferative disorder, namely a pre-B ALL. Also in patient 2, pain returned and became progressive over a few weeks. A total body MRI showed a progressive disease with intermediate signal intensity on STIR and hypointense signaling on T1-weighted images at different vertebrae and the sacral bone. A second bone marrow puncture at the crista returned to be negative. Guided by the MRI images a bone biopsy was performed in the sacral bone and was compatible with the diagnosis of an ALCL. Conclusion: CRMO remains a diagnosis of exclusion in patients with osteoarticular pain and inflammation. In case of persistent and/or progressive pain, the physician should keep a high index of suspicion for malignancy. Total body MRI can precisely define the characteristics and extent of the bone lesions (aspect and localization) as well as help in choosing the optimal localization for bone marrow puncture and/or bone biopsy.

Background TNF-α antagonism with anti-TNF-α MoAb (Infliximab, Centocor, USA) or soluble TNF-α receptors (Etanercept, Immunex, USA), has emerged as a promising therapeutic tool for refractory chronic arthritis. Both drugs are now licensed for the treatment of refractory RA but experience with TNF-α antagonisers in JIA is limited. Objectives We report the use of Infliximab in 3 patients with systemic JIA and polyarthritis. Methods LS (18 yrs) and JD (11 yrs), girls with systemic-onset JIA at the age of 11 and 3, had persistent, destructive polyarthritis. AP (10 yrs), a boy with systemic-onset JIA at the age of 5 had persistent systemic activity as well as severe polyarthritis. All 3 failed NSAID, corticosteroids, (high-dose) MTX and CsA treatment and suffered from severe growth impairment and osteoporosis. All patients started Infliximab therapy at 3 mg/kg (weeks 0, 2, 6 and then 8-weekly). Active joint number (AJN), limited joint number (LJN), visual analogue scale for global well being (VASg) and pain (VASp), Childhood Health Assessment Questionnaire (CHAQ), serum CRP and serum IL-6 were assessed. Results At present, LS completed 26, JD 38 and AP 86 treatment weeks. LS experienced a manifest decrease in AJN (17 to 1). LJN was unchanged (8). Functional scores decreased markedly: VASg 78 to 10, VASp 45 to 10, CHAQ 1.2 to 0.3. CRP decreased (15 to 3 mg/l) and steroids were tapered from 6 to 3 mg daily. JD showed a similar response: AJN and LJN decreased rapidly (38 to 5 and 41 to 7). VASg, VASp and CHAQ all dropped markedly: 50 to 15, 50 to 10 and 2.1 to 1.4. CRP and ESR decreased (22 to 5 mg/L and 51 to 26 mm/hr). Steroid dose was kept at 4 mg daily. AP experienced a decrease in AJN (9 to 3) and in LJN (12 to 4) during the first 18 weeks. As systemic inflammation persisted, Infliximab dose was increased to 5, later to 10 mg/kg. Whereas AJN and LJN decreased further to 0 and 2, systemic symptoms and the acute phase response persisted: CRP and ESR fluctuated (15–148 mg/l and 45 ? 183 mm/h, respectively). Functional scores varied and reflected the increasing discomfort of preexisting joint damage. Steroid dose was tapered from 12 to 7 mg daily. Infliximab was safe and well tolerated in all 3 patients: possible adverse reactions were fever (AP, once) and upper respiratory tract infection (AP three, JD once). TNF-α blockade with Infliximab in these patients with systemic-onset polyarticular JIA induced a rapid, sustained control of polyarthritis, with concomitant improvement of function, global well being and pain and decrease in biochemical inflammation. Systemic inflammation, however, did not respond to TNF-α blockade. This was evident in patient AP whose articular disease clearly responded but who had a persistent acute phase response with persistently elevated levels of CRP and IL-6. Conclusion Infliximab is promising for the treatment of JIA. The observed dissociation between response of articular and systemic disease indicates that different cytokine networks may operate in systemic and articular inflammation of JIA.

IntroductionIn clinical laboratories, capillary zone electrophoresis(CZE) has emerged as a novel technique for the rapidand effective separation of serum proteins (1, 2). CZEhas the advantage of automation, improved precision,and a faster turn-around time.CZE uses ultraviolet detection at 214 nm for directprotein quantification through the quantification of thepeptide bonds, whereas with conventional methods,protein quantification is based on dye binding. This dif-ference between CZE and conventional methods withrespect to the technique that is used to quantify proteinhas an impact on the reference range. For example,when compared to agarose or cellulose acetate elec-trophoresis, CZE gave substantially higher referenceintervals for the α1-globulin fraction (2). This discrep-ancy is related to the fact that the high sialic acid con-tent of α1-acid glycoprotein interferes with the bindingof dyes used to quantify this protein fraction.Although several studies have reported referenceranges for CZE in healthy adults (2–6), no such data isavailable for children. Studies in children using con-ventional zone electrophoresis (7, 8) showed age-de-pendent changes in the reference range.In children there is little need to perform electrophore-sis for the diagnosis and monitoring of myeloma, whichis the main indication for performing serum proteinelectrophoresis. However, serum protein electrophoresis is also useful for assessing overall plasma proteinstatus. Although the major serum proteins can be mea-sured by quantitative assays, serum electrophoresis is acheap and valuable initial procedure for detecting ab-normalities of the serum proteins. It is of use in the labo-ratory investigation of acute and chronic inflammatorydiseases, in protein-losing syndromes, and in the detec-tion of protein deficiencies (9, 10). As there is a correla-tion between the sum of the individually measured im-munoglobulins and the electrophoretic γ-globulin level,serum electrophoresis is also of use as an initial screen-ing test for the detection of hypogammaglobulinemiaand of primary immunodeficiency (10–12). It is unusualto find hypogammaglobulinemia if the γ-globulin levelis normal on serum electrophoresis (9).The aim of our study was to establish CZE referenceintervals for the five electrophoretic serum protein fractions in Caucasian children.

Interleukin-1β (IL-1β) plays a key role in the pathogenesis of systemic juvenile idiopathic arthritis (SJIA). Efficacy and safety of canakinumab (CAN), a selective, fully human, anti- IL-1β monoclonal antibody, have been demonstrated in 2 phase III trials. Here we present 12-week results of a post-hoc pooled analysis.