Showing papers by "Reinhard Hohlfeld published in 2008"

Multiple Sclerosis Therapy Consensus Group (MSTCG) Basic and escalating immunomodulatory treatments in multiple sclerosis: Current therapeutic recommendations

Abstract: ■ Abstract This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.

Basic and escalating immunomodulatory treatments in multiple sclerosis: current therapeutic recommendations.

Abstract: This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.

The immunopathogenesis of myasthenia gravis.

Abstract: Publisher Summary Myasthenia gravis (MG) is a human autoimmune disease. Autoantibodies against neuromuscular antigens play a key role in the pathogenesis of MG, and the detection and monitoring of these antibodies is essential for the clinical management of myasthenic patients. This chapter reviews the immunopathogenesis of MG. The chapter provides an overview of some fundamental principles of immunology, and then addresses the role of antibodies, T cells, immunogenetic aspects, and thymus. The relevant animal models of MG, the risk factors of MG and associations with other immunological diseases are discussed. Complement system mediates destruction of the postsynaptic membrane of the neuromuscular junction. The detection of autoantibodies against acetylcholine receptor (AChR) is a key element for making the diagnosis of autoimmune MG. CD4+ helper T cells are crucially involved in the immunopathogenesis of MG. MG is associated with other autoimmune diseases (e.g., rheumatoid arthritis, thyroid disease) pointing to a general autoimmune predisposition of MG patients conferred by unknown genes. The thymus is thought to play an important role in MG pathogenesis. Patients with thymic tumors carry a markedly increased risk of developing myasthenia gravis. The features of experimental autoimmune myasthenia gravis (EAMG) vary with the species and strain, source of AChR, use of adjuvants, and immunization schedules. Epidemiological data indicates that the prevalence of late onset MG is increasing. If aging is an independent risk factor for the development of MG is yet to be determined.

Multiple sclerosis and the TNFRSF1A R92Q mutation: clinical characteristics of 21 cases.

Abstract: Objective: Tumor necrosis factor receptor 1–associated periodic syndrome (TRAPS) is an autosomal dominantly inherited autoinflammatory disorder resulting from mutations in the TNFRSF1A gene, which encodes the p55 receptor for tumor necrosis factor α. We recently identified the R92Q mutation encoded by exon 4 in six patients with multiple sclerosis (MS) who reported at least two symptoms suggestive of TRAPS. The current study presents the characteristics of a larger cohort of MS patients carrying this mutation. Methods: Clinical and laboratory parameters, including human leukocyte antigen (HLA)-DR15 status, were evaluated, and genetic testing was performed. Whenever possible, family members were also invited for interview and mutation analysis. Results: Twenty TNFRSF1A R92Q carriers had MS according to the McDonald criteria, and 1 had clinically isolated syndrome. The majority of patients had typical onset and features of MS. Nine patients carried an HLA-DR15 haplotype. All individuals showed TRAPS-compatible symptoms, which consisted mainly of myalgias, arthralgias, headache, severe fatigue, and skin rashes; were milder than usually described; and appeared mainly in adulthood. Most patients experienced severe side effects during immunomodulatory therapy for MS. Seventeen family members carried the identical mutation, and 15 of them reported symptoms suggestive of TRAPS. Conclusion: In most cases with multiple sclerosis (MS) and coexisting tumor necrosis factor receptor 1–associated periodic syndrome (TRAPS), features of MS were quite typical, whereas TRAPS presented mostly without the fever episodes observed in childhood. The penetrance of the R92Q mutation in affected family members was higher than reported. We recommend careful observation of MS patients with coexisting TRAPS with regard to unexpected side effects of immunomodulatory therapies. GLOSSARY: ANA = antinuclear antibody; CIS = clinically isolated syndrome; COP = Copaxone; CRP = C-reactive protein; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; FLS = flu-like symptoms; FMF = familial Mediterranean fever; GC = glucocorticoid; GI = gastrointestinal; HLA = human leukocyte antigen; IFN = interferon beta; MIM = Mendelian Inheritance in Man; MS = multiple sclerosis; MSSS = Multiple Sclerosis Severity Score; NK = not known; NSAID = nonsteroidal anti-inflammatory drug; OCB = oligoclonal band; PI = progression index; RA = rheumatoid arthritis; SAA = serum amyloid A; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor; TRAPS = tumor necrosis factor receptor 1–associated periodic syndrome; WBC = white blood cell.

Open use of natalizumab. Neutralising antibodies and clinical data

Abstract: Background. Since June 2006 natalizumab has been available for use as monotherapy in relapsing-remitting MS with high disease activity. The AFFIRM study showed the occurrence of persisting and neutralising antinatalizumab antibodies (nAb) in 6% of the patients. We present data revealing the number of nAb-positive patients assessed in our independent laboratory. Additionally we provide retrospective clinical data on the efficacy of natalizumab as escalating immunotherapy. Patients and Methods. Blood samples of patients treated with natalizumab in Germany were tested for nAb using an enzyme-linked immunosorbent assay. If nAb were detectable at a single time point, the according patients were categorised as transiently positive. They were diagnosed as persistently positive if they had nAb at two or more time points which were at least 6 weeks apart. The treating neurologists sending the serum samples were asked to provide clinical data of their patients. Results. Forty-seven of 593 samples (9.1%) were nAb-positive, 19 of them (3.7%) persistently positive and two (0.3%) transiently. Twenty-six patients (5%) were not retested for nAb, as we did not receive material for confirmatory analysis. Infusion-related adverse events were reported for 53 patients (10.3%). Averages of 2.6 relapses per year were reported previous to natalizumab therapy and 0.3 per year during natalizum-ab therapy. Conclusion. During natalizumab therapy, testing for nAb should be strongly considered for further therapy decisions and in cases of suspected allergic reaction. Basically the obtained data compare with those of the AFFIRM study. Natalizumab is applied as escalating therapy in MS according to the recommendations of the MSTKG, and it seems to match the expectations in open-label use.