Rheumatoid Arthritis: Niehues T

Niehues T, Horneff G, Michels H, Höck MS, Schuchmann L, Anonymous00331, Anonymous00332. · Pediatric Immunology and Rheumatology, Department of Pediatric Oncology, Hematology and Immunology, Centre for Child Health, Heinrich-Heine-University, Dusseldorf, Germany. · Rheumatol Int. · Pubmed #15688190 No free full text.

Abstract: Juvenile idiopathic arthritis (JIA) is the most common diagnosis in children and adolescents with rheumatic disorders. In many children and adolescents, JIA is successfully treated with non-steroidal anti-inflammatory drugs (NSAID) and physiotherapy. However, in a significant number of cases the disease is resistant to this therapy, and treatment with "second line" disease-modifying antirheumatic drugs (DMARDs) is required. Methotrexate (MTX) is frequently referred to as "first-choice second-line agent" for the treatment of JIA. To increase drug safety, the Working Groups for Children and Adolescents with Rheumatic Diseases in Germany (AGKJR) and Pediatric Rheumatology Austria have initiated the formulation of evidence-based recommendations. Evidence is based on consensus expert meetings, a MEDLINE search with the key words "Methotrexate" and "juvenile arthritis" limited to age 0-18 years, standard textbooks and review articles, data from the central registry of the German Research Center for Rheumatic Diseases (Deutsches Rheumaforschungszentrum Berlin DRFZ), experience with MTX in adults with rheumatoid arthritis (RA), and recommendations of the German Society of Rheumatology (DGRh). Based on these data, evidence and recommendations are graded, and evidence-based recommendations for the use of MTX in children and adolescents with rheumatic disease are presented.

Niehues T, Feyen O, Telieps T. · Zentrum für Kinder- und Jugendmedizin, Helios Klinikum Krefeld, Akademisches Lehrkrankenhaus der Heinrich-Heine-Universität Düsseldorf, Krefeld, Deutschland. · Z Rheumatol. · Pubmed #18309499 No free full text.

Abstract: There are various explanations for the development of juvenile idiopathic arthritis (JIA).Gene changes in the immune system can predispose to JIA and regulation of the immune system is crucial in the pathogenesis. The adaptive, acquired immune system probably plays a central role. Thus, in the case of JIA a conspicuous population of highly activated T-cells can be found in the synovia. B-cells are also involved, as indicated by positive ANA titers in JIA patients. Regulatory T-cells (Tregs) attempt to prevent the expansion of autoreactive T-cells.However, the natural or the innate immune system also plays a role. Thus a disorder of the inflammasome could underlie the cause of JIA with systemic onset. The interaction between congenital and adaptive immune system shows that a distinct spatial and temporal separation between the two immune systems is becoming increasingly difficult. An infection- and virus-related immune reaction could also be the cause of JIA. Proinflammatory cytokines are of proven significance in pathogenesis in terms of how they are released under stress, for example.New genomic and proteomic techniques are able to produce individualized profiles for each patient and allow for increasingly fine separation between subtypes, thus improving therapeutic possibilities.

Niehues T, Lankisch P. · Department of Pediatric Oncology, Hematology and Immunology, Pediatric Immunology and Rheumatology, Centre for Child Health, Heinrich-Heine-University, Düsseldorf, Germany. · Paediatr Drugs. · Pubmed #17154642 No free full text.

Abstract: Juvenile idiopathic arthritis (JIA) is one of the most common rheumatic diseases in childhood. In a significant number of JIA cases the disease is resistant to therapy with NSAIDs, intra-articular corticosteroid injections, and physiotherapy, and methotrexate is used as a second-line agent. The efficacy of methotrexate therapy in children with JIA has been demonstrated in prospective controlled trials and this agent appears to have slightly superior efficacy compared with leflunomide. Data from randomized studies indicate a starting dose of 10-15 mg/m(2)/week orally. The dose of parenteral methotrexate can be increased to 15-20 mg/m(2)/week. Combination therapy with methotrexate and an NSAID is recommended. However, there are still no data on when to initiate methotrexate in JIA and how long children should be treated. The most common adverse effects are aversion to the drug and nausea. In the case of minor adverse effects the use of folic acid at a dosage of 1 mg/day is feasible. In JIA, daily folate supplementation has only been studied in one small heterogeneous cohort with a very short observation period and, at present, a general recommendation on daily folate supplementation cannot be made. In summary, methotrexate is seen by many pediatric rheumatologists as the first-choice, second-line drug; there is good evidence of its efficacy in JIA. However, in light of the recent introduction of biologic agents, the place of methotrexate in the treatment of JIA may have to be redefined in the coming years.

Niehues T, Horneff G, Michels H, Sailer Höck M, Schuchmann L. · Pädiatrische Immunologie und Rheumatologie Klinik für Kinder-Onkologie-Hämatologie und Immunologie Zentrum für Kinder- und Jugendmedizin, Heinrich-Heine-Universität Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. · Z Rheumatol. · Pubmed #15112095 No free full text.

Abstract: Juvenile idiopathic arthritis (JIA) is the most common diagnosis in children and adolescents with rheumatic disorders. In many children and adolescents, JIA is successfully treated with nonsteroidal antiinflammatory drugs (NSAR) and physiotherapy. Still, in a significant number of cases the disease is resistant to this therapy and treatment with "second line" disease modifying antirheumatic drugs (DMARDs) is required. Methotrexate (MTX) is frequently referred to as "first choice second line agent" for the treatment of JIA. However, there are considerable differences among pediatric rheumatologists on how and when to use MTX. To increase drug safety, the Working Group for Children and Adolescents with Rheumatic Diseases in Germany (AGKJR) and the Working Group Pediatric Rheumatology Austria have initiated the formulation of evidence-based recommendations. Evidence is based on consensus expert meetings, a MEDLINE search with the key words "Methotrexate" and "juvenile arthritis" limited to age 0-18 years, standard textbooks and review articles, data from the central registry of the German Research Center for Rheumatic Diseases (Deutsches Rheumaforschungszentrum Berlin), experience with MTX in adults with rheumatoid arthritis (RA) and recommendations of the German Society of Rheumatology (DGRh). Based on these data, evidence and recommendations are graded and evidence-based recommendations for the use of MTX in children and adolescents with rheumatic disease are presented.

Guellac N, Niehues T. · Zentrum für Kinder und Jugendmedizin, HELIOS Klinikum Krefeld. · Klin Padiatr. · Pubmed #18949678 No free full text.

Abstract: Treatment of Juvenile Idiopathic Arthritis (JIA) has improved quality of life in children and adolescents suffering from JIA. However, it varies considerably from caregiver to caregiver. Therefore a standardisation of care on the basis of consensus treatment recommendations offers the chance to further improve the quality of care for children and adolescents with JIA. We aimed to establish an interdisciplinary, evidence-based treatment guideline for JIA based on the existing guideline from 2005. METHODS: We did a systematic literature analysis in PUBMED with the key words "juvenile idiopathic (rheumatoid) arthritis" and "therapy". As limits in PUBMED we used: humans, published in the last 3 years, all child 0-18 years, clinical trial. Studies relating to diagnosis of JIA, Uveitis, vaccination, transition and rofexocibe were excluded. Authors of the 2005 guideline and representatives nominated by different societies were invited to attend the consensus conferences which were hosted by a professional moderator. Following societies were invited: Berufsverband der Kinder- und Jugendärzte (BVKJ), Deutsche Gesellschaft für Kinder- und Jugendmedizin (DGKJ), Deutsche Gesellschaft für Rheumatologie (DGRh), Deutsche Ophthalmologische Gesellschaft (DOG), Deutsche Rheuma-Liga Bundesverband, Verein zur Förderung und Unterstützung rheumatologisch erkrankter Kinder und deren Eltern, Vereinigung für Kinderorthopädie, Zentraler Verband der Physiotherapeuten und Krankengymnasten (ZVK). Consensus conferences took place in Düsseldorf on May 9th and August 1st 2007 and were each attended by more than 95% of the nominated representatives Finally, statements were confirmed in a Delphi method. RESULTS AND CONCLUSION: Consensus statements regarding drug therapy, symptomatic and surgical management of JIA were compiled and judged strictly by the criteria of Evidence-Based Medicine (EBM).

Feyen O, Telieps T, Schmitz I, Niehues T. · Department of Pediatric Oncology, Hematology and Clinical Immunology, Jeffrey Modell Immunodeficiency Center, University Children's Hospital Düsseldorf, Germany. · Klin Padiatr. · Pubmed #18949671 No free full text.

Abstract: BACKGROUND: Altered apoptosis can lead to autoimmune diseases such as systemic lupus erythematosus (SLE). Juvenile idiopathic arthritis (JIA) is another autoimmune disease characterized by autoinflammation. During this process activated T-cells accumulate in the synovial fluid. We hypothesized that resistance to CD95-mediated apoptosis could contribute to autoimmune phenotypes. PATIENTS/METHOD: We isolated highly activated T cells (CD45RO+ and CD95+) by magnetic separation from healthy controls, JIA patients and patients with other autoimmune diseases. In these purified cells, apoptosis was induced by stimulation with recombinant human soluble CD95 ligand (rhsCD95L) or dexamethasone and analyzed by flow cytometry. In addition, cleavage and expression of apoptosis mediators (Caspase-8 and -3) and regulators (FLIP, Bcl-2, Bcl-xL) were analyzed in mononuclear cells using immunoblot technique. RESULTS: Apoptosis upon CD95 stimulation, but not dexamethasone treatment, was reduced in JIA patients and patients with other autoimmune diseases compared to healthy controls. Additionally we observed a non-canonical cleavage pattern of Caspase-8 resulting in a p22 fragment and high expression of FLIP in SFMCs of patients with JIA. CONCLUSION: Expression and cleavage of proteins of the CD95 pathway is altered in JIA providing a possible explanation for resistance against death receptor-mediated apoptosis. Dexamethasone-induced apoptosis, however, is intact arguing against a general defect in apoptosis. The implications of the p22 fragment regarding apoptosis have to be further analyzed. The strong expression of FLIPShort in SFMCs may as well result from the highly activated status of the cells or be a feature of autoimmunity.

Winterhalter S, Niehues T. · Department of Ophthalmology, University Hospital Düsseldorf, Germany. · Klin Padiatr. · Pubmed #18949668 No free full text.

Abstract: Treatment of childhood uveitis associated with juvenile idiopathic arthritis (JIA) is a challenge for both, ophthalmologists and pediatricians. In this study, we use the tools of evidence based medicine (EBM) to analyse studies concerning disease-modifying antirheumatic drugs (DMARD)/ immunosuppressive drugs and tumor necrosis factor alpha (TNFalpha) blocking agents. Most experience among DMARD's/ immunosuppressive drugs has been obtained with methotrexate (MTX) in juvenile idiopathic arthritis. However, controlled studies in uveitis are still missing, so that treatment with MTX and all other immunosuppressive drugs (ciclosporine A, azathioprine, mycophenolate mofetil) only reaches an evidence level III (expert opinion, clinical experience or descriptive study). Studies on TNFalpha-blocking agents reach an evidence level II-III, depending on the substance. In future, MTX will have to be examined in comparison to the new biological substance classes (e.g., tumor necrosis factor-alpha-blockers) for the treatment of uveitis in juvenile idiopathic arthritis. Controlled studies which have led to the approval of drugs for JIA are needed for uveitis in order to have the most effective and safe therapy for children with uveitis, who do not respond to conventional therapy with local and systemic steroids.

Feyen O, Lueking A, Kowald A, Stephan C, Meyer HE, Göbel U, Niehues T. · Department of Pediatric Oncology, Hematology and Clinical Immunology, Jeffrey Modell Immunodeficiency Center, University Children's Hospital Düsseldorf, 40225, Düsseldorf, Germany. · Anal Bioanal Chem. · Pubmed #18344017 No free full text.

Abstract: Tumor necrosis factor-alpha inhibitors are widely and successfully used to treat rheumatic diseases. However, significant side effects have been reported. To detect the potential off-target activities of such inhibitors we characterized two therapeutic antibodies (adalimumab, infliximab) and one receptor fusion protein (etanercept) on protein biochips (UNIchip AV-400) containing a printed serial dilution of tumor necrosis factor-alpha and about 384 different human proteins. Etanercept binds to ten proteins (affinity: 20-33% of tumor necrosis factor-alpha recognition), and six of these proteins are related to ribosomal proteins. Interestingly, adalimumab binds to the same six proteins related to ribosomal proteins (affinity: 12-18%) as well as to four proteins crucially involved in ribosomal protein synthesis. Alignment of protein sequences indicates no significant sequence homology between these ten proteins bound by the biological drugs with the highest off-target activities. Taken together, our in vitro results demonstrate that a significant number of proteins are recognized by tumor necrosis factor-alpha inhibitors and are related to ribosome biogenesis.

Knipp S, Feyen O, Ndagijimana J, Niehues T. · Department of Pediatrics, Pediatric Immunology and Rheumatology, Heinrich Heine University of Düsseldorf, 40225, Düsseldorf, Germany. · Rheumatol Int. · Pubmed #12739040 No free full text.

Abstract: We hypothesise that T-cell apoptosis and the percentage of T cells expressing molecules involved in apoptosis modulation (CD95, CD28) are altered at the inflammation site and in peripheral blood (PB) of children with juvenile idiopathic arthritis (JIA). Paired JIA samples of synovial fluid (SF) and PB ( n=7) and PB samples from age-matched normal children ( n=23) were analysed immediately ex vivo. Apoptosis was measured by detection of phophatidylserine (PS) externalisation on T cells. CD95 or CD28 was detected by FACS, and soluble CD95 and CD95 ligand levels were detected by enzyme-linked immunosorbent assay (ELISA). In SF, the mean percentage of apoptotic T cells was somewhat higher than in PB. However, the percentages of T cells expressing CD95 and soluble CD95 levels were markedly higher in SF (CD4 cells 96+/-2%, CD8 91+/-6%, soluble CD95 6,420+/-2,571 pg/ml) than in PB (CD4 32+/-10%, CD8 36+/-9%, soluble CD95 4,296+/-2,142 pg/ml). Peripheral blood T-cell apoptosis in JIA (CD4 20+/-8%, CD8 42+/-19%) was higher than in the control group (CD4 5+/-2%, CD8 9+/-6%). Interestingly, the percentage of PB CD4 cells expressing CD28 was lower in JIA than controls. In conclusion, systemic T-cell apoptosis was higher in JIA while a substantial number of SF T cells survived locally, despite the fact that almost all cells express CD95.