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.

[Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action]. / Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie : Substanzspezifische Relevanz und aktuelle Handlungsempfehlungen.

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.

[Current aspects of therapy conversion for multiple sclerosis]. / Aktuelles zur Therapieumstellung bei Multipler Sklerose.

In recent years the approval of new substances has led to a substantial increase in the number of course-modifying immunotherapies available for multiple sclerosis. Therapy conversion therefore represents an increasing challenge. The treatment options sometimes show complex adverse effect profiles and necessitate a long-term and comprehensive monitoring. This article presents an overview of therapy conversion of immunotherapies for multiple sclerosis in accordance with the recommendations of the Disease-Related Competence Network for Multiple Sclerosis and the German Multiple Sclerosis Society as well as the guidelines on diagnostics and therapy for multiple sclerosis of the German Society of Neurology and the latest research results. At the present point in time it should be noted that no studies have been carried out for most of the approaches for therapy conversion given here; however, the recommendations are based on theoretical considerations and therefore correspond to recommendations at the level of expert consensus, which is currently essential for the clinical daily routine.

[Multiple sclerosis and microbiota. From genome to metagenome?]. / Multiple Sklerose und Mikrobiota. Vom Genom zum Metagenom?

The individual risk of contracting multiple sclerosis (MS) is determined by genetic predisposition as well as environmental factors. In monozygotic twins the concordance rate for MS is approximately 30 % indicating that environmental factors are even more important than genetic factors. Observations in a T-cell receptor-transgenic, spontaneous mouse model strongly point to an important contribution of the individual gut microbiome (microbiota). Mice maintained in a germ-free environment are completely protected from experimental autoimmune encephalomyelitis (EAE) in this model, whereas mice that are kept under normal conditions spontaneously develop a relapsing-remitting central nervous system (CNS) disease which is astoundingly similar to human MS. It appears that the autoimmune reaction against CNS tissue is "remotely controlled" by the gut microbiota. This may be explained by the facts that the microbiota influences the gut-associated lymphoid tissue (GALT) and, vice versa, the GALT regulates systemic immunity. The precise role of the microbiota in MS remains to be clarified. New methods of DNA sequencing and bioinformatics allow the analysis of very complex bacterial metagenomes. If individual microbial risk profiles can be identified this would provide completely new perspectives for the prophylaxis and therapy of MS.

[Immunotherapies for multiple sclerosis : review and update]. / Immuntherapie der multiplen Sklerose : Überblick und Update.

Multiple sclerosis (MS) is an inflammatory, presumably autoimmune disease affecting the central nervous system. Early stages of the disease are characterized by conspicuous inflammation of the white and grey matter. During later stages, presumably secondary neurodegeneration leads to physical disability progression. Over the last decade increasingly effective therapeutic options have been approved. Currently 11 immunomodulatory or immunosuppressive therapies targeting relapse rate, disease progression and paraclinical disease activity are available, mostly for relapsing forms of MS. However, the ideal of "precision medicine" is still in the distant future since biomarkers for individualized treatment are lacking. For implementation of risk-management plans to minimize the risk of severe side effects, interdisciplinary collaboration between neurologists and internists is essential. In this review article we summarize practical aspects of the implemented risk-management plans, and discuss possible side effects and special caveats of the three new immunotherapies teriflunomide, dimethyl fumarate, and alemtuzumab. This article is based on, among others, the recently updated guidelines of the German Society of Neurology. Particular attention is given to the risks of new therapies, monitoring, and on special aspects needing attention when changing treatments. Teriflunomide, dimethyl fumarate, and alemtuzumab expand treatment options for relapsing-remitting MS. Treatment selection should take into consideration the safety profile of the substance, previous and concomitant diseases, and other individual factors. This requires in-depth consultation and individual assessment of current disease activity, the potential efficacy of the therapy, and the possible risks and side effects.

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.

Familial Mediterranean fever-associated mutation pyrin E148Q as a potential risk factor for multiple sclerosis.

BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. OBJECTIVE: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. METHODS: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R RESULTS: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q (n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS (p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. CONCLUSION: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.

Antibodies to MOG are transient in childhood acute disseminated encephalomyelitis.

OBJECTIVE: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. METHODS: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. RESULTS: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. CONCLUSIONS: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.

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.

Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS.

BACKGROUND: The oral immunomodulator fingolimod (FTY720) has recently been shown to be highly effective in relapsing-remitting multiple sclerosis (MS). Fingolimod is a functional antagonist of the sphingosine-1-phosphate receptor 1 and thereby inhibits sphingosine-1-phosphate-dependent lymphocyte egress from secondary lymphoid tissues, resulting in a pronounced lymphopenia in the peripheral blood. The effects of fingolimod treatment on the CSF of patients with MS have not been studied so far. METHODS: We analyzed the leukocyte count, albumin quotient, immunoglobulin G (IgG) index, and oligoclonal bands in the CSF of fingolimod-treated patients with MS. Moreover, we performed immunophenotyping of CSF and peripheral blood leukocytes by flow cytometry. The results were compared to those from treatment-naive or natalizumab-treated patients with MS and patients with other inflammatory and noninflammatory neurologic diseases. RESULTS: Fingolimod therapy significantly decreased CSF leukocyte counts, but had little impact on the extent of intrathecal IgG synthesis and presence of oligoclonal bands in the CSF. Fingolimod decreased the proportion of CSF CD4+ T cells but to a lesser extent than in the peripheral blood. While fingolimod strongly reduced B cells in the periphery, it had little impact on B cells in the CSF. The percentage of CSF CD8+ T cells, NK cells, and monocytes increased compared to treatment-naive patients. The CD4+/CD8+ T-cell ratio in CSF reversed in most of the patients. CONCLUSION: Fingolimod treatment has a profound impact on CSF, which to some extent differs from the peripheral effects of the drug.

[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.

[Oral fingolimod in multiple sclerosis: therapeutic modulation of the sphingosine-1-phosphate system]. / Orales Fingolimod bei Multipler Sklerose : Therapeutische Modulation des Sphingosin-1-Phosphat-Systems.

In this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-ß1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.

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.