Frank Dressler

Immaturity, perinatal inflammation, and retinopathy of prematurity: A multi-hit hypothesis

OBJECTIVE To explore the relationship among markers of infection/inflammation in their association with retinopathy of prematurity (ROP). METHODS We studied clinical characteristics and 4 single nucleotide polymorphisms in infection/inflammation-associated genes in a group of 73 children with a gestational age<32 weeks. Forty-four children (60%) had ROP, of whom 13 (30% of those with ROP) progressed to stage 3 ROP. No child had grade 4 or 5 ROP. We employed both descriptive and analytic statistical methods. RESULTS Clinical variables of infection/inflammation were consistently associated with an increased risk of ROP. Among infants with ROP, they were also associated with progression to ROP grade 3. Genetic markers were not associated with ROP occurrence, but with progression to high grade disease. In tri-variable analyses exploring the effects of gestational age <29 weeks, clinical chorioamnionitis (CAM) and neonatal systemic inflammatory response syndrome (SIRS) on ROP occurrence, low gestational age was the most important antecedent, while additional individual or joint exposure to SIRS and CAM add appreciably to this risk of progression to high grade disease. CONCLUSION Both antenatal and neonatal exposure to inflammation appear to contribute to the increased ROP risk in preterm infants.

Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis : a randomised trial

BACKGROUND Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. METHODS We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedmans test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. FINDINGS Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. INTERPRETATION Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. FUNDING Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).

The Ped-APS Registry: the antiphospholipid syndrome in childhood

In recent years, antiphospholipid syndrome (APS) has been increasingly recognised in various paediatric autoimmune and nonautoimmune diseases, but the relatively low prevalence and heterogeneity of APS in childhood made it very difficult to study in a systematic way. The project of an international registry of paediatric patients with APS (the Ped-APS Registry) was initiated in 2004 to foster and conduct multicentre, controlled studies with large number of paediatric APS patients. The Ped-APS Registry is organised as a collaborative project of the European Forum on Antiphospholipid Antibodies and Juvenile Systemic Lupus Erythematosus Working Group of the Paediatric Rheumatology European Society. Currently, it documents a standardised clinical, laboratory and therapeutic data of 133 children with antiphospholipid antibodies (aPL)-related thrombosis from 14 countries. The priority projects for future research of the Ped-APS Registry include prospective enrolment of new patients with aPL-related thrombosis, assessment of differences between the paediatric and adult APS, evaluation of proinflammatory genotype as a risk factor for APS manifestations in childhood and evaluation of patients with isolated nonthrombotic aPL-related manifestations.

Distinct Effects of Methotrexate and Etanercept on the B Cell Compartment in Patients With Juvenile Idiopathic Arthritis

B cells have been shown to play an important role in the pathogenesis of rheumatoid arthritis and juvenile idiopathic arthritis (JIA). Current treatments include the disease‐modifying antirheumatic drugs methotrexate (MTX) and tumor necrosis factor α inhibition with etanercept. This study was undertaken to determine how these drugs influence the B cell compartment in patients with JIA.

2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Juvenile Dermatomyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative

To develop response criteria for juvenile dermatomyositis (DM).

Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study.

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.

OP0059 A Randomized Trial in New Onset Juvenile Dermatomyositis: Prednisone Versus Prednisone Plus Cyclosporine Versus Prednisone Plus Methotrexate

Background Data regarding the safety and efficacy of treatment regimens for juvenile dermatomyositis (JDM) tends to be from anecdotal, small, uncontrolled, non-randomized case series. Objectives This randomized trial was aimed to find out the treatment regimen associated with the lowest occurrence of flare and the lowest drug related toxicity. Methods Children with newly diagnosed JDM were randomized in an open fashion to receive one of 3 different therapeutic approaches: prednisone (PDN) versus PDN plus methotrexate (MTX) versus PDN plus Cyclosporine A. The overall hypothesis to be tested in this trial was that the early introduction of combination therapy of corticosteroids and either MTX or CsA will prove more effective and safe than corticosteroids alone in the treatment of JDM. Primary outcome measures after 6 months of treatment: response rate according to the Paediatric Rheumatology International Trials Organisation (PRINTO) provisional definition of improvement in the 3 arms (20% improvement in at least 3 core set variables with no more than 1 of the remaining variables, (muscle strength excluded), worsened by > 30%). The PRINTO JDM core set variables are: 1) muscle strength by the mean of the Childhood Myositis Assessment Scale (CMAS); 2) physician’s global assessment of disease activity on a 10 cm VAS ; 3) global disease activity assessment by the mean of the Disease Activity Index (DAS); 4) parent’s/patient’s global assessment of overall well-being on a 10 cm VAS; 5) functional ability assessment by the mean of the Childhood Health Assessment Questionnaire (CHAQ); 6) health-related quality of life assessment. Primary outcome measures after 24 months of treatment: a) time to inactive disease; b) time to major therapeutic changes because of inefficacy/flare/adverse events. Results 138/139 randomized patients were included in the efficacy dataset. There were 81/138 females (59%) with a median age at onset of 7.4 years (1st-3rd quartiles 1.1-15.4) and a median disease duration of 2.8 months (1.4-5.3). Frequency of response at 6 months was for 24/46 (52.2%) for PDN, 31/46 (67.4%) for PDN+CSA and 34/46 (73.9%) for PDN+MTX (p 0.082). Time to inactive disease in the combination group (PDN+CSA or PDN+MTX) was significantly shorter than that of PDN alone (p 0.031). Time to major therapeutic changes in the combination group (PDN+CSA or PDN+MTX) was significantly longer than that of PDN alone (p 0.009). Total number of adverse events were 57/276 (20.7%) in the PDN group, 141/276 (51.1%) in PDN+CSA and 78/276 (28.3%) in PDN+MTX (p < 0.0001). Skin and subcutaneous tissue disorders, and nervous system disorders were statistically more frequent in PDN+CSA (p 0.0015, p 0.039 respectively). Conclusions Combined therapy with PDN and either CSA or MTX was more effective than with PDN alone. However the safety profile favour the combination with MTX toward that with CSA. Disclosure of Interest None Declared

Correlation of Secretory Activity of Neutrophils With Genotype in Patients With Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin‐encoding MEFV mutations. Patients present with recurrent but self‐limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil‐derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.

Secretory Activity of Neutrophils Correlates With Genotype in Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin‐encoding MEFV mutations. Patients present with recurrent but self‐limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil‐derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF.

Lyme-Arthritis bei Kindern und Jugendlichen

Lyme arthritis is one of the manifestations of Lyme disease and is caused by infection with Borrelia burgdorferi sensu lato. This article reviews the current knowledge regarding the epidemiology, etiology and pathogenesis as well as the clinical manifestations, the diagnosis, treatment and prognosis with special emphasis on children and adolescents.ZusammenfassungDie Lyme-Arthritis ist eine Manifestation der durch die Infektion mit Borrelia burgdorferi sensu lato verursachten Lyme-Borreliose. In dieser Arbeit werden die aktuellen Erkenntnisse zur Epidemiologie, Ätiologie und Pathogenese sowie zu den klinischen Manifestationen und deren Diagnose, Behandlung und Prognose dargestellt, unter besonderer Berücksichtigung des Kinder- und Jugendalters.AbstractLyme arthritis is one of the manifestations of Lyme disease and is caused by infection with Borrelia burgdorferi sensu lato. This article reviews the current knowledge regarding the epidemiology, etiology and pathogenesis as well as the clinical manifestations, the diagnosis, treatment and prognosis with special emphasis on children and adolescents.