Publications by authors named "Frank Dressler"

22 Publications

  • Page 1 of 1

Myositis-specific autoantibodies and their associated phenotypes in juvenile dermatomyositis: data from a German cohort.

Clin Exp Rheumatol 2020 Oct 29. Epub 2020 Oct 29.

German Rheumatism Research Center, Leibniz Institute, Berlin, Germany.

Objectives: To describe a German cohort of patients with juvenile dermatomyositis (JDM) and to evaluate clinical manifestations, disease course and prognosis in JDM patients with a certain myositis-specific autoantibody.

Methods: Cross-sectional data on patients with JDM documented in the National Paediatric Rheumatologic Database in Germany between 2014 and 2016 were analysed. In a subgroup of the cohort, MSAs were determined with a commercial multiplex array, and a retrospective chart review was conducted to specify the clinical phenotype and patient outcome.

Results: The total cohort consisted of 196 patients with JDM (mean age 12.2±4.0 years, mean disease duration 5.1±3.8 years, 70% female). Apart from typical skin changes and muscle weakness, 41% of patients also had arthritis and/or contractures, 27% had calcinosis and approximately 10% had interstitial lung disease. Immunoblot testing was performed on the sera of 91 (46%) patients, detecting MSAs in 44% of patients. Patient groups with specific MSAs differed in clinical characteristics such as calcinosis, dysphagia, and lung and joint involvement. The extent of muscle weakness evaluated by the Childhood Myositis Assessment Scale was significantly associated with an increased level of creatine kinase. Patients with anti-MDA5 were particularly affected by polyarthritis of the small joints. After 5 years, 51 patients of the MSA cohort (56.0%) achieved an inactive disease state, 12/51 (23.5%) were off therapy.

Conclusions: Patients with JDM in Germany show a broad spectrum of clinical manifestations that can be grouped into homogeneous groups using MSA, which also helps to predict the course and prognosis of the disease.
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October 2020

Long-term safety and effectiveness of etanercept in JIA: an 18-year experience from the BiKeR registry.

Arthritis Res Ther 2020 10 29;22(1):258. Epub 2020 Oct 29.

Division of Paediatric Rheumatology, Sankt Augustin Asklepios Children's Hospital, 53757 Sankt Augustin, Germany.

Background: At present, etanercept represents the most commonly prescribed biologic agent for juvenile idiopathic arthritis (JIA) treatment. Children and adolescents with JIA are often treated with etanercept over long periods, sometimes even into adulthood. The objectives of this analysis were to determine the long-term safety of etanercept compared to a biologic-naïve cohort and to assess the long-term treatment response upon continuous etanercept exposure using data from the German biologics registry (BiKeR).

Methods: JIA patients newly exposed to etanercept were documented in the BiKeR registry from January 2001 to March 2019, and baseline characteristics, effectiveness, and safety parameters were analysed. Response to treatment was assessed according to 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), JADAS-defined minimal disease activity and remission, JIA-American College of Rheumatology (ACR) improvement criteria, and ACR-inactive disease definition. Safety assessments were based on adverse event (AE) reports.

Results: A total of 2725 new etanercept users with a diagnosis of JIA were registered. Of these, etanercept was received as a first-line biologic by 95.8% and as monotherapy without concomitant methotrexate by 31.5%. After nine years on continuous treatment, 68.1% of patients presented minimal disease activity, 43.1% JADAS-defined remission on drug, and 36.6% ACR-inactive disease. JIA-ACR30/50/70/90 response rates were still 82/79/71/54% after nine years of treatment. Overall, 2053 AEs (34.3/100PY), including 226 serious AEs (SAE, 3.8/100PY), were observed upon etanercept, compared to 1345 AEs [35.6/100PY; p = 0.3] and 52 SAEs (1.4/100PY; p = 0.0001) in the biologic-naïve cohort. Respective exposure-adjusted rates for etanercept and biologic-naïve patients were 0.9/100PY and 0.2/100PY (p = 0.0001) for serious infections, 0.4/100PY and 0.1/100PY (p = 0.01) for zoster reactivation, 0.3/100PY and 0.03/100PY (p = 0.015) for inflammatory bowel disease, and 1.9/100PY and 1.4/100PY (p = 0.09) for uveitis. Three and two malignancies were documented in the etanercept and biologic-naïve groups, as well as three and one deaths, respectively.

Conclusions: No new safety signal was observed, especially no increased risk for malignancies or autoimmune disorders other than inflammatory bowel disease. However, SAEs and serious infections, though infrequent, were more often reported on etanercept than in biologic-naïve patients. In addition, etanercept demonstrated a long-term maintenance of clinical benefits up to nine years of continuous treatment.
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http://dx.doi.org/10.1186/s13075-020-02326-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597050PMC
October 2020

COVID-19 related reduction in pediatric emergency healthcare utilization - a concerning trend.

BMC Pediatr 2020 09 7;20(1):427. Epub 2020 Sep 7.

Department of Pediatric Pneumology, Allergology, and Neonatology, Hannover Medical School, Carl-Neuberg-Straße 1, D - 30625, Hannover, Germany.

Background: The COVID-19 pandemic has disrupted healthcare systems worldwide. In addition to the direct impact of the virus on patient morbidity and mortality, the effect of lockdown strategies on health and healthcare utilization have become apparent. Little is known on the effect of the pandemic on pediatric and adolescent medicine. We examined the impact of the pandemic on pediatric emergency healthcare utilization.

Methods: We conducted a monocentric, retrospective analysis of n = 5,424 pediatric emergency department visits between January 1st and April 19th of 2019 and 2020, and compared healthcare utilization during the pandemic in 2020 to the same period in 2019.

Results: In the four weeks after lockdown in Germany began, we observed a massive drop of 63.8% in pediatric emergency healthcare utilization (mean daily visits 26.8 ± SEM 1.5 in 2019 vs. 9.7 ± SEM 1 in 2020, p < 0.005). This drop in cases occurred for both communicable and non-communicable diseases. A larger proportion of patients under one year old (daily mean of 16.6% ±SEM 1.4 in 2019 vs. 23.1% ±SEM 1.7 in 2020, p < 0.01) and of cases requiring hospitalisation (mean of 13.9% ±SEM 1.6 in 2019 vs. 26.6% ±SEM 3.3 in 2020, p < 0.001) occurred during the pandemic. During the analysed time periods, few intensive care admissions and no fatalities occurred.

Conclusions: Our data illustrate a significant decrease in pediatric emergency department visits during the COVID-19 pandemic. Public outreach is needed to encourage parents and guardians to seek medical attention for pediatric emergencies in spite of the pandemic.
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http://dx.doi.org/10.1186/s12887-020-02303-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475725PMC
September 2020

Biologic Therapies in Polyarticular Juvenile Idiopathic Arthritis. Comparison of Long-Term Safety Data from the German BIKER Registry.

ACR Open Rheumatol 2020 Jan 24;2(1):37-47. Epub 2019 Nov 24.

Asklepios Klinik Sankt Augustin, Sankt Augustin, Germany, and University of Cologne, Cologne, Germany.

Objective: Biologics have an important role in the treatment of juvenile idiopathic arthritis (JIA). Long-term safety data are limited. Direct comparison of different agents regarding occurrence of adverse events (AEs), especially of rare events, requires large quantities of patient years. In this analysis, long-term safety with regard to AE of special interest (AESI) was compared between different biologics.

Methods: Patients with nonsystemic JIA were selected from the German BIKER registry. Safety assessments were based on AE reports. Number of AEs, serious AEs, and 25 predefined AESIs, including medically important infection, uveitis, inflammatory bowel disease, cytopenia, hepatic events, anaphylaxis, depression, pregnancy, malignancy, and death, were analyzed. Event rates and relative risks were calculated using AEs reported after first dose through 70 days after last dose.

Results: A total of 3873 patients entered the analysis with 7467 years of exposure to biologics. The most common AESIs were uveitis (n = 231) and medically important infections (n = 101). Cytopenia and elevation of transaminases were more frequent with tocilizumab (risk ratio [RR] 8.0, 95% confidence interval [CI] 4.2-15, and RR 4.7, 95% CI 1.8-12.2, respectively). Anaphylactic events were associated with intravenous route of administration. In patients ever exposed to biologics, eight malignancies were reported. Six pregnancies have been documented in patients with tumor necrosis factor inhibitors. No death occurred in this patient cohort during observation.

Conclusion: Surveillance of pharmacotherapy as provided by the BIKER registry is an import approach, especially for long-term treatment of children. Overall, tolerance was acceptable. Differences between biologics were noted and should be considered in daily patient care.
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http://dx.doi.org/10.1002/acr2.11091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957918PMC
January 2020

Long-term surveillance of biologic therapies in systemic-onset juvenile idiopathic arthritis: data from the German BIKER registry.

Rheumatology (Oxford) 2020 09;59(9):2287-2298

Centre for Paediatric Rheumatology, Department of Paediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin.

Objective: Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed.

Methods: Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model.

Results: Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept.

Conclusion: Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care.
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http://dx.doi.org/10.1093/rheumatology/kez577DOI Listing
September 2020

Development of practice and consensus-based strategies including a treat-to-target approach for the management of moderate and severe juvenile dermatomyositis in Germany and Austria.

Pediatr Rheumatol Online J 2018 Jun 25;16(1):40. Epub 2018 Jun 25.

German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen Department of Dermatology, Oberammergau Center for Rheumatic Diseases, Oberammergau, Germany.

Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM.

Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements.

Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease.

Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.
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http://dx.doi.org/10.1186/s12969-018-0257-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019723PMC
June 2018

Familial Mediterranean fever in children and adolescents: factors for colchicine dosage and predicting parameters for dose increase.

Rheumatology (Oxford) 2017 09;56(9):1597-1606

Pediatric Pneumology and Immunology, Charité University Medicine Berlin.

Objectives: The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future.

Methods: Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA.

Results: The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease.

Conclusion: Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future.
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http://dx.doi.org/10.1093/rheumatology/kex222DOI Listing
September 2017

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.

Ann Rheum Dis 2017 May;76(5):782-791

Istituto Giannina Gaslini, Pediatria II - Reumatologia, PRINTO, Genoa, Italy.

To develop response criteria for juvenile dermatomyositis (DM). We analysed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique. Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute per cent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (p=0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (p<0.006). The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute per cent change in core set measures, with thresholds for minimal, moderate, and major improvement.
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http://dx.doi.org/10.1136/annrheumdis-2017-211401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517365PMC
May 2017

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.

Arthritis Rheumatol 2017 05 6;69(5):911-923. Epub 2017 Apr 6.

Istituto Giannina Gaslini, Pediatria II - Reumatologia, PRINTO, Genoa, Italy.

Objective: To develop response criteria for juvenile dermatomyositis (DM).

Methods: We analyzed the performance of 312 definitions that used core set measures from either the International Myositis Assessment and Clinical Studies Group (IMACS) or the Paediatric Rheumatology International Trials Organisation (PRINTO) and were derived from natural history data and a conjoint analysis survey. They were further validated using data from the PRINTO trial of prednisone alone compared to prednisone with methotrexate or cyclosporine and the Rituximab in Myositis (RIM) trial. At a consensus conference, experts considered 14 top candidate criteria based on their performance characteristics and clinical face validity, using nominal group technique.

Results: Consensus was reached for a conjoint analysis-based continuous model with a total improvement score of 0-100, using absolute percent change in core set measures of minimal (≥30), moderate (≥45), and major (≥70) improvement. The same criteria were chosen for adult DM/polymyositis, with differing thresholds for improvement. The sensitivity and specificity were 89% and 91-98% for minimal improvement, 92-94% and 94-99% for moderate improvement, and 91-98% and 85-86% for major improvement, respectively, in juvenile DM patient cohorts using the IMACS and PRINTO core set measures. These criteria were validated in the PRINTO trial for differentiating between treatment arms for minimal and moderate improvement (P = 0.009-0.057) and in the RIM trial for significantly differentiating the physician's rating for improvement (P < 0.006).

Conclusion: The response criteria for juvenile DM consisted of a conjoint analysis-based model using a continuous improvement score based on absolute percent change in core set measures, with thresholds for minimal, moderate, and major improvement.
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http://dx.doi.org/10.1002/art.40060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577002PMC
May 2017

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

Arthritis Rheumatol 2016 12;68(12):3010-3022

University Children's Hospital, Muenster, Germany.

Objective: 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.

Methods: Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1β, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1β were also analyzed in 128 clinically and genetically characterized patients with FMF.

Results: In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease.

Conclusion: The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.
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http://dx.doi.org/10.1002/art.39784DOI Listing
December 2016

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

Lancet 2016 Feb 30;387(10019):671-8. Epub 2015 Nov 30.

Istituto Giannina Gaslini, Pediatria II, Reumatologia, PRINTO Coordinating Centre, Genoa, Italy; Università di Genova, Dipartimento di Pediatria, Genoa, Italy.

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 Friedman's 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).
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http://dx.doi.org/10.1016/S0140-6736(15)01021-1DOI Listing
February 2016

Chronic arthritis in a boy with Cernunnos immunodeficiency.

Clin Immunol 2014 Sep 12;154(1):47-8. Epub 2014 Jun 12.

Department of Pediatric Pulmonology, Allergy and Neonatology, Hannover Medical School, Carl-Neuberg-Strasse 1, OE6710, D-30625 Hannover, Germany.

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http://dx.doi.org/10.1016/j.clim.2014.06.003DOI Listing
September 2014

Distinct effects of methotrexate and etanercept on the B cell compartment in patients with juvenile idiopathic arthritis.

Arthritis Rheumatol 2014 Sep;66(9):2590-600

Hannover Medical School, Hannover, Germany.

Objective: 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.

Methods: B cell subpopulations and follicular helper T (Tfh) cells in the peripheral blood of JIA patients were investigated by multicolor flow cytometry. Serum immunoglobulin and BAFF levels were determined by enzyme-linked immunosorbent assay.

Results: There was a significant decrease in transitional B cells and significantly lower serum immunoglobulin levels in patients receiving MTX than in untreated patients and those receiving etanercept. In contrast, etanercept treatment had no effect on most of the B cell subpopulations, but resulted in significantly lower BAFF levels and increased numbers of Tfh cells. Thus, our findings indicate an unexpected and previously unknown direct effect of low-dose MTX on B cells, whereas etanercept had a more indirect influence.

Conclusion: Our results contribute to a better understanding of the potency of MTX in autoantibody-mediated autoimmune disease and present a possible mechanism of prevention of the development of drug-induced antibodies to biologic agents. The finding that MTX and etanercept affect the B cell compartment differently supports the notion that combination therapy with etanercept and MTX is more effective than monotherapy.
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http://dx.doi.org/10.1002/art.38736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288311PMC
September 2014

Performance of Birmingham Vasculitis Activity Score and disease extent index in childhood vasculitides.

Clin Exp Rheumatol 2012 Jan-Feb;30(1 Suppl 70):S162-8. Epub 2012 May 14.

IRCCS G. Gaslini, Pediatria II, Reumatologia, PRINTO, Genova, Italy.

Objectives: To evaluate the performance of the Birmingham Vasculitis Activity Score (BVAS) v3 and the Disease Extent Index (DEI) for the assessment of disease activity in 4 primary childhood (c-) systemic vasculitides.

Methods: Patients fulfilling the EULAR/PRINTO/PRES (Ankara) c-vasculitis classification criteria for Henoch-Schönlein purpura (HSP), childhood (c) polyarteritis nodosa (c-PAN), c-Wegener's granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) with disease duration at the time of diagnosis ≤3 months were extracted from the PRINTO database. The performance of the BVAS and DEI were examined by assessing convergent validity, the pattern of disease involvement, and responsiveness. We also evaluated alternative unweighted scoring methods for both tools.

Results: The analysis set included 796 patients with 669 HSP, 80 c-PAN, 25 c-WG and 22 c-TA. The median age at diagnosis was 6.9 years (6.6-12) and median delay in making the diagnosis from the onset of signs/symptoms was 0.01 (0.003-0.027) years. A strong correlation was found between the BVAS and DEI (rs=0.78) while correlation with the physician global assessment was moderate (rs=0.48) with BVAS and poor with DEI (rs=0.25). Both the BVAS and DEI sub-scores and total scores were able to descrive the disease involvement in the 4 childhood vasculitides. Responsiveness was large (>1.5) for both tools. The performance characteristics of the BVAS and DEI with the unweighted methods were comparable.

Conclusions: This study demonstrates that both the BVAS and DEI are valid tools for the assessment of the level of disease activity in a large cohort of childhood acute and chronic vasculitides.
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August 2012

Lung function in children and adolescents with juvenile idiopathic arthritis during long-term treatment with methotrexate: a retrospective study.

Clin Exp Rheumatol 2012 Mar-Apr;30(2):302-7. Epub 2012 Apr 13.

Division of Pediatric Pneumology, Allergology and Neonatology, Dept. of Pediatrics, Hannover Medical School, Hannover, Germany.

Objectives: Methotrexate may cause severe adverse pulmonary side-effects in adults with rheumatoid arthritis. Our aim was to examine the long-term effect of MTX on lung function in patients with juvenile idiopathic arthritis (JIA).

Methods: We retrospectively reviewed the charts of all 68 patients with JIA treated with MTX at our centre over a 14-year period. Results of annual pulmonary function tests (PFT) were compared using paired t-tests adjusted by Bonferroni correction and by linear regression analysis.

Results: The patients in our study had taken MTX for a median of 6.7 years with a median cumulative dose of 3219 mg. In a subgroup of 37 patients PFT had been performed before the onset of MTX. In this subgroup there was a significant decrease of mean mid-expiratory flow (MMEF) after 3 years (-14.0%, p<0.001) of MTX. Diffusion capacity of the lung for carbon monoxide (DLCO) was reduced after the third year (-12.4%, p=0.001). In the total group there was a decrease in MMEF between years 3 and 4 after MTX onset (-13.5%, p=0.001). Forced expiratory volume (FEV1) showed a slight rise between years 4 and 5 (+5.5%, p=0.003). All other parameters remained without significant changes. There was no correlation of PFT results and cumulative MTX dose or JIA subtype. None of our patients developed clinically relevant lung disease.

Conclusions: In summary we found some declines of MMEF and DLCO during long-term treatment with MTX. Overall our data confirm the relative safety of long-term MTX treatment in patients with JIA. We conclude that further data on the development of pulmonary function in patients receiving MTX therapy would be helpful.
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July 2012

Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial.

Ann Rheum Dis 2010 Aug 4;69(8):1479-83. Epub 2010 Jun 4.

IRCCS G Gaslini, Pediatria II, Reumatologia, PRINTO, Genova, Italy.

Objectives: To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis.

Methods: Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology International Trials Organization (PRINTO) MTX trial. Bivariate and logistic regression analyses were used to identify baseline predictors of poor response according to the American College of Rheumatology pediatric (ACR-ped) 30 and 70 criteria.

Results: In all, 405/563 (71.9%) of patients were women; median age at onset and disease duration were 4.3 and 1.4 years, respectively, with anti-nuclear antibody (ANA) detected in 259/537 (48.2%) patients. With multivariate logistic regression analysis, the most important determinants of ACR-ped 70 non-responders were: disease duration > 1.3 years (OR 1.93), ANA negativity (OR 1.77), Childhood Health Assessment Questionnaire (CHAQ) disability index > 1.125 (OR 1.65) and the presence of right and left wrist activity (OR 1.55). Predictors of ACR-ped 30 non-responders were: ANA negativity (OR 1.92), CHAQ disability index > 1.14 (OR 2.18) and a parent's evaluation of child's overall well-being < or = 4.69 (OR 2.2).

Conclusion: The subgroup of patients with longer disease duration, ANA negativity, higher disability and presence of wrist activity were significantly associated with a poorer response to a 6-month MTX course.
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http://dx.doi.org/10.1136/ard.2009.120840DOI Listing
August 2010

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

Early Hum Dev 2009 May 13;85(5):325-9. Epub 2009 Feb 13.

Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA 02111, USA.

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.
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http://dx.doi.org/10.1016/j.earlhumdev.2008.12.010DOI Listing
May 2009

Popliteal venous thrombosis in juvenile arthritis with Baker cysts: report of 3 cases.

Pediatr Rheumatol Online J 2008 Jul 24;6:12. Epub 2008 Jul 24.

Department of Pediatrics, Medizinische Hochschule Hannover, Hannover, Germany.

Three pediatric patients with different illnesses leading to knee arthritis and large Baker cysts and additional calf swelling are reported. Calf swelling was due to true popliteal venous thrombosis and not to the much more common cause of pseudothrombophlebitis. Careful ultrasound examination can differentiate these two causes of calf swelling. Even though all our patients had risk factors for thrombophilia, we do not recommend routine thrombophilia work-up for all arthritis patients in the absence of thrombosis.
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http://dx.doi.org/10.1186/1546-0096-6-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533307PMC
July 2008

Osteoporosis in juvenile idiopathic arthritis--a practical approach to diagnosis and therapy.

Eur J Pediatr 2007 Aug 14;166(8):775-84. Epub 2007 Apr 14.

Department of Pediatric Pneumology and Immunology, Charite University Medicine, Berlin, Germany.

In all subgroups of juvenile idiopathic arthritis, a decrease in bone mass has been described in a high percentage of children. Recently, new pathogenetic concepts have identified muscle mass as the strongest predictor of bone mass and bone is now recognized as part of the musculoskeletal system. In addition, the sophisticated use of bone densitometry in pediatrics, including new measurement techniques, has provided the tools for a reliable assessment. A standardized diagnostic approach to the musculoskeletal system, including prophylaxis and therapy, is, therefore, mandatory in all children with JIA who do not achieve rapid remission. In this review, diagnostic and therapeutic options are being described and possibilities to incorporate them into clinical practice are suggested.
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http://dx.doi.org/10.1007/s00431-007-0484-1DOI Listing
August 2007

Juvenile polyarteritis: results of a multicenter survey of 110 children.

J Pediatr 2004 Oct;145(4):517-22

Department of Pediatrics, Hacettepe University, Ankara, Turkey.

Objective: To characterize pediatric patients who had been diagnosed with polyarteritis nodosa (PAN) through necrotizing vasculitis of the small and mid-size arteries or those with characteristic findings on angiograms data were collected.

Study Design: Pediatricians were asked to classify their patients into one of the four suggested groups for juvenile PAN. Twenty-one pediatric centers worldwide participated with 110 patients.

Results: The girl:boy ratio was 56:54, with a mean age of 9.05 +/- 3.57 years. The cases were classified as: 33 (30%) cutaneous PAN; 5 (4.6%) classic PAN associated with hepatitis B surface antigen (HBs Ag); 9 (8.1%) microscopic polyarteritis of adults associated with antineutrophil cytoplasmic antibodies (ANCA); and 63 (57.2%) systemic PAN. Cutaneous PAN was disease confined to the skin and musculoskeletal system. All patients with HBs Ag-associated classic PAN were diagnosed with renal angiograms. Antiviral treatment was administered in most cases. Microscopic PAN patients had pulmonary-renal disease, in combination or separately. ANCA was present in 87%, and 2 patients progressed to end-stage renal failure. Patients classified with systemic PAN had multiple system involvement, almost all had constitutional symptoms, and all had elevated acute phase reactants. Corticosteroids and cyclophosphamide were the first choices of immunosuppressive treatment. The overall mortality was 1.1%.

Conclusions: There were remarkable differences among pediatric patients with PAN, with different clinical manifestations and overall better survival and lower relapse rates when compared with adults.
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http://dx.doi.org/10.1016/j.jpeds.2004.06.046DOI Listing
October 2004