Myelin-oligodendrocyte-glycoprotein (MOG) autoantibodies as potential markers of severe optic neuritis and subclinical retinal axonal degeneration.

Antibodies against conformation-dependent epitopes of myelin-oligodendrocyte-glycoprotein (MOG-abs) are present in subgroups of neuromyelitis optica spectrum disorder (NMOSD), recurrent optic neuritis (rON), multiple sclerosis (MS), and anti-NMDAR encephalitis. Using optical coherence tomography (OCT) we assessed whether MOG-abs might serve as potential marker of retinal axonal degeneration. We investigated a clinically heterogeneous cohort of 13 MOG-abs-positive patients (4 MOG-abs-positive rON, 4 MOG-abs-positive adult MS, 3 MOG-abs-positive relapsing encephalomyelitis, 2 MOG-abs-positive aquaporin-4-abs-negative NMOSD). As controls, we studied 13 age, sex and ON episode(s)-matched MOG-abs and aquaporin-4-abs-negative (AQP4-abs-negative) MS patients and 13 healthy controls (HC). In addition, we investigated 19 unmatched AQP4-abs-positive MOG-abs-negative NMOSD subjects. Considering all eyes, global pRNFL [in µm, mean (SD)] was significantly reduced in MOG-abs-positive patients [72.56 (22.71)] compared to MOG-abs-negative MS [80.81 (13.55), p = 0.0128], HCs [103.54 (8.529), p = 0.0014] and NMOSD [88.32 (18.43), p = 0.0353]. Non ON eyes from MOG-abs-positive subjects showed significant subclinical atrophy of temporal pRNFL quadrants. Microcystic macular edema (MME) was observed only in eyes of MOG-abs-positive (24%) and AQP4-abs-positive NMOSD (5.6%), but not in MOG-abs-negative MS or HC (p < 0.01). MOG-abs may serve as potential marker of retinal degeneration. Specifically, MOG-abs-related OCT features predominate in temporal pRNFL quadrants (resembling the MS retinal pattern), might be more severe than AQP4-abs-positive NMOSD, indicate subclinical pathology, and may be associated with MME.

Co-occurrence of two cases of progressive multifocal leukoencephalopathy in a natalizumab "infusion group".

We observed two cases of progressive multifocal leukoencephalopathy (PML) that occurred in the same "infusion group". The group consisted of four patients with relapsing-remitting multiple sclerosis (RRMS) who had been treated with natalizumab (NAT) in the same medical practice for more than four years at the same times and in the same room, raising concerns about viral transmission between members of the infusion group. DNA amplification and sequence comparison of the non-coding control region (NCCR) of JC virus (JCV) present in cerebrospinal fluid (CSF) samples from PML patients #1 and #2 revealed that the amplified JCV sequences differed from the JCV archetype. The NCRR of the viral DNA was unique to each patient, arguing against the possibility of viral transmission between patients. Statistical considerations predict that similar co-occurrences of PML are likely to happen in the future.

Long-term follow-up of patients with neuromyelitis optica after repeated therapy with rituximab.

BACKGROUND: Neuromyelitis optica (NMO) is a severe autoimmune disease targeting optic nerves and spinal cord. The monoclonal anti-CD20 B-cell antibody rituximab is an emerging therapeutic option in NMO. However, neither long-term efficacy or safety of rituximab, nor the correlation between B-cell counts, B-cell fostering cytokines, aquaporin-4 antibodies (AQP4-ab), and disease activity in NMO, have been investigated prospectively. METHODS: We performed a prospective long-term cohort study of 10 patients with NMO who were treated up to 5 times with rituximab as a second-line therapy. Clinical examinations, B-cell counts, and serum concentrations of BAFF (B-cell activating factor of the TNF family; also called TNFSF13b), APRIL (a proliferation-inducing ligand; also called TNFSF13), AQP4-ab, and immunoglobulin levels were measured every 3 months. RESULTS: Repeated treatment with rituximab led to sustained clinical stabilization in most patients with NMO. Disease activity correlated with B-cell depletion, but not clearly with AQP4-ab or levels of APRIL. BAFF levels increased after application of rituximab and indicated persisting efficacy of the drug but did not correlate with disease activity. Overall, rituximab was well-tolerated even after up to 5 consecutive treatment courses; however, we observed several severe adverse reactions. CONCLUSION: Our data indicate that long-term therapy with rituximab is effective in NMO as a second-line therapy and has an acceptable safety profile. Retreatment with rituximab should be applied before reappearance of circulating B cells. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that repeated doses of rituximab result in stabilization in most patients.

[Progressive multifocal leukoencephalopathy under natalizumab. Initial possibilities for risk stratification?]. / Progressive multifokale Leukenzephalopathie unter Natalizumab. Erste Möglichkeiten einer Risikostratifizierung?

Natalizumab (Tysabri®) is the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS) but while treatment is highly efficient, it carries the risk of progressive multifocal leukoencephalopathy (PML). Based on reports of confirmed cases of PML, the risk of PML might increase beyond 24 months of treatment. Thus, attempts to stratify patients treated with natalizumab into those carrying higher or lower risk for developing PML are currently being undertaken. Among these strategies JC virus serology might potentially be the first tool available. As a large variety of methods have been published resulting in controversial results for JC virus seroprevalence, standardized testing will be mandatory when applying this method in clinical practice. In addition, risk management strategies for the seropositive majority of patients need to be redefined and optimized further.

Drug-induced Sweet's syndrome after mitoxantrone therapy in a patient with multiple sclerosis.

We report a 55-year-old male patient with secondary progressive multiple sclerosis who developed an acute febrile syndrome with fever, neutrophilia and tender erythematous plaques and papules on his upper extremities after his fifth mitoxantrone infusion. Infectious, haematological and rheumatological diseases were ruled out, but skin biopsy showed neutrophilic infiltrations in the dermis consistent with Sweet's syndrome. Treatment with oral corticosteroids led to prompt improvement of systemic and cutaneous symptoms. To our knowledge, this is the first report of a patient with Sweet's syndrome after mitoxantrone therapy. Clinicians should be aware of Sweet's syndrome in patients with otherwise unexplained acute febrile illness and erythematous skin rash in association with mitoxantrone therapy. Skin biopsy helped to exclude other diseases and confirmed Sweet's syndrome.

Concurrent TNFRSF1A R92Q and pyrin E230K mutations in a child with multiple sclerosis.

We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutations in two genes which predispose to hereditary autoinflammatory disorders. We speculate that these mutations contribute to early multiple sclerosis manifestation and enhance the inflammatory damage inflicted by the autoimmune response.

[Progressive multifocal leukoencephalopathy. Undesirable side effect of immunotherapy]. / Progressive multifokale Leukenzephalopathie. Unerwünschte Nebenwirkung einer Immuntherapie.

As new cases arise of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with the monoclonal antibody natalizumab, a critical discussion about risks and advantages of this specific kind of immunotherapy appears necessary. Practical consequences and treatment options are addressed based on current concepts of PML's pathogenesis in patients treated with natalizumab. Critical patient selection based on risk:benefit considerations, limited therapy regimens, early diagnosis of PML by clinical and paraclinical criteria, and therapeutic perspectives for treating PML are discussed. The risk of PML in patients with MS needs to be continually monitored and should be reduced with all means available to ensure optimal outcome.

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

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 alpha. 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.

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

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.

Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis.

BACKGROUND: Natalizumab, a humanized anti-alpha4 integrin monoclonal antibody, reduces relapses and disease progression in patients with multiple sclerosis (MS). Whereas its presumed mode of action is inhibition of T cell/monocyte entry into the brain, little is known about its specific effect on B cells, which are increasingly recognized to participate in MS pathogenesis. METHODS: We obtained serial blood samples from 17 patients before and during natalizumab therapy for relapsing-remitting MS for up to 16 months, and blood samples from 10 untreated patients with MS and 13 healthy donors. We determined numbers of mature and immature lymphocyte subsets by flow cytometry for CD3, CD4, CD8, CD19, CD138, and CD10 in 111 samples. We analyzed marker transcripts for immature hematopoietic cells by quantitative PCR for CD34, Vprebeta1 (pre-B lymphocyte gene 1), and DNTT (terminal deoxynucleotidyltransferase) in 65 samples. RESULTS: Natalizumab therapy increased CD19(+) mature B cells more than other lymphocytes/monocytes in blood (2.8-fold versus 1.3-1.8-fold increase in cells/microL; p < 0.01). Even greater was the increase of immature CD19(+)CD10(+) pre-B cells (7.4-fold; p < 0.01). This pattern remained stable during treatment for up to 16 months. Transcripts of lymphocyte precursors (Vprebeta1 and DNTT) were elevated more than transcripts for CD34. CONCLUSIONS: Circulating B cells and especially pre-B cells are most prominently elevated among the studied immune cell subsets, raising the possibility that the effects and side effects of natalizumab are partly mediated by actions on B cells.

Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity.

B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.

Corticosteroids for myasthenia gravis.

BACKGROUND: Although widely accepted as an appropriate immunosuppressive therapy, the efficacy of glucocorticosteroid treatment has only rarely been tested in controlled studies. OBJECTIVES: To assess the efficacy of glucocorticosteroids or adrenocorticotrophic hormone (ACTH) medication in autoimmune myasthenia gravis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register in July 2004, MEDLINE (from January 1966 to June 2004) and EMBASE (from January 1980 to June 2004). We also checked the bibliographies in reviews and the randomised trials and contacted their authors to identify additional published and unpublished data. SELECTION CRITERIA: From the articles identified we selected those open or controlled studies which allowed us to assess the outcome of treated and untreated patients at definite endpoints. Types of studies: quasi-randomised or randomised controlled trials. TYPES OF PARTICIPANTS: patients with myasthenia gravis of all ages and all degrees of severity. Types of interventions: any form of glucocorticosteroids or adrenocorticotrophic hormone treatment. Types of outcome measures:Primary outcome(1) improvement after at least three months in either the weakest muscles or all muscles. Secondary outcomes(1) proportion of patients improved after at least six months(2) proportion of patients in remission(3) number of episodes of worsening during the first six months(4) acetylcholine receptor antibody titres after at least three months of therapy. DATA COLLECTION AND ANALYSIS: Three authors extracted the data from the selected articles and one other checked them. MAIN RESULTS: A trial of adrenocorticotrophic hormone (43 patients) did not show any advantage compared with placebo for the treatment of ocular myasthenia gravis. Two double-blind trials compared prednisone with placebo for generalised myasthenia gravis. In the first (13 patients), the improvement was slightly greater in the prednisone group at six months. In the second (20 patients) which was a short-term trial, the improvement was significantly greater at two weeks. Two trials compared glucocorticosteroids with azathioprine (41 and 10 patients respectively). In one of these the rate of treatment failure was greater in the prednisone group. In a trial of glucocorticosteroids versus intravenous immunoglobulin (33 patients) no differences in treatment responses were encountered during a treatment period of 14 days. An open trial (39 patients) evaluating different corticosteroid doses revealed a shorter time to improvement in the high-dose group. However only limited evidence can be drawn from the available randomised controlled trials due to numerous and important methodological flaws. AUTHORS' CONCLUSIONS: Limited evidence from randomised controlled trials suggests that corticosteroid treatment offers significant short-term benefit in myasthenia gravis compared with placebo. This supports the conclusions of observational studies and expert opinion. Limited evidence from randomised controlled trials does not show any difference in efficacy between corticosteroids and either azathioprine or intravenous immunoglobulin.

[Diagnosis and treatment of multiple sclerosis. Update, 2003]. / Diagnose und Therapie der Multiplen Sklerose. Update 2003.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. The etiology of MS is not yet fully understood. Besides of genetic predisposition and environmental factors autoimmune mechanisms seem to play a major role in the pathogenesis of MS. Therapy of MS therefore comprises mainly immunomodulatory and immuno-suppressive therapeutic concepts. Interferon beta (Avonex, Rebif, Betaferon/Betaseron) and Glatirameracetate (Copaxone) offer effective therapeutic options for the long-term treatment of relapsing-remitting MS. With Mitoxantron (Ralenova) being recently approved by the EMEA for the treatment of secondary-progressive and progressive-relapsing MS an effective therapeutic option is now available also for this group of patients. The standard treatment for acute MS continues to be the intravenous administration of high-dose methylprednisolone. Several promising new agents (Antegren, Statins) are currently under clinical examination and could expand the spectrum of available therapeutic strategies soon. Recent and ongoing trials as well as upcoming studies on MS therapy are summarized in this review.

The recognition, diagnosis and management of cerebral vasculitis: a European survey.

We have completed a survey of European neurological practice concerning cerebral vasculitis. Twenty-nine respondents from 15 countries provided information concerning the diagnosis and management. The results confirmed the anticipated low frequency of the disease, but also illustrated the power of any putative collaborative effort. Interestingly, there was a wide variation in clinical practice, in particular concerning the perceived importance of cerebral angiography as a diagnostic test and the very common use of steroids as first-line treatment, rather than more potent immunosuppressive agents. This variation is probably to be explained at least, in part, by the absence of any firm evidence base to inform clinical practice. A European collaborative effort--in which there has emerged considerable interest--offers a realistic opportunity to generate sound clinical evidence and thence scientifically robust practical guidelines.

[Treatment of multiple sclerosis with glatiramer acetate. Current aspects of mechanisms of action, pharmacokinetics, adverse effect profile and clinical studies]. / Behandlung der Multiplen Sklerose mit Glatiramer-Azetat. Aktuelles zu Wirkungsmechanismen, Pharmakokinetik, Nebenwirkungsprofil und Studiensituation.

Glatiramer acetate (GA, Copaxone), a standardized mixture of synthetic polypeptides, has now been approved also in Germany for the treatment of relapsing-remitting multiple sclerosis (RR-MS). After it had been shown effective in suppression of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), it was evaluated in several clinical studies. In these studies, GA could alter the natural history of MS by both reducing the relapse rate and affecting disability. The clinical therapeutic effect of GA was consistent with the effect on magnetic resonance imaging-defined disease activity and burden in a recent multicenter study. As a daily standard dose, 20 mg of GA is injected subcutaneously. The induction of GA-reactive T-helper 2-like regulatory suppressor cells is thought to be the main mechanism of action. The most common adverse effects are mild injection site reactions. A remarkable but rare adverse effect is the only transient immediate post-injection systemic reaction manifested by flushing, chest tightness, palpitations, and dyspnea. Antibodies to GA which are induced during GA treatment do not interfere with its clinical effects.