Lack of efficacy of mitoxantrone in primary progressive Multiple Sclerosis irrespective of pharmacogenetic factors: a multi-center, retrospective analysis.

BACKGROUND: Mitoxantrone is used on an off-label basis in primary progressive MS (PPMS). ABC-transporter-genotypes are associated with therapeutic response in relapsing/secondary progressive MS (RP/SPMS). OBJECTIVE: To evaluate potential pharmacogenetic response markers for mitoxantrone in PPMS. METHODS: 41 mitoxantrone-treated PPMS-patients, 155 mitoxantrone-treated RP/SPMS-patients and 43 PPMS-controls were retrospectively assessed for clinical therapy-response and in correlation with four single-nucleotide-polymorphisms in ABCB1- and ABCG2-genes. RESULTS: 53.7% PPMS-patients were mitoxantrone-responders, in comparison to 78.1% of RP/SPMS-patients (p=0.039). There was no association between genotype and treatment response. CONCLUSION: Our data discourages the use of mitoxantrone in PPMS regardless of pharmacogenetic response markers previously described in RP/SPMS.

Treatment failure of intrathecal baclofen and supra-additive effect of nabiximols in multiple sclerosis-related spasticity: a case report.

Multiple sclerosis (MS)-related spasticity is associated with disability and impairment in quality of life. We report on a patient with secondary progressive MS and spastic tetraparesis (Expanded Disability Status Scale score 8.5). The right arm exhibited flexor spasticity resulting in functional disability despite multimodal symptomatic treatment. Intrathecal baclofen led to side effects despite decreasing efficacy. Low-dose nabiximols improved spasticity and function with recovery of daily-life activities and spasticity-related symptoms. Reduction of intrathecal baclofen ameliorated adverse drug reactions. Add-on cannabinoid therapy was effective in therapy-refractory spasticity with supra-additive effect in combining intrathecal baclofen and nabiximols, hypothetically explained by mutually complementing mechanisms of action.

Advancing therapeutic options in multiple sclerosis with neuroprotective properties.

Central nervous system (CNS) inflammation has been considered to be the main pathological feature of multiple sclerosis (MS). However, the complexity of this autoimmune disorder also comprises neurodegenerative processes that may occur within acute phases of inflammation, yet also temporally independent and outside of inflammatory lesions or even in so-called normal appearing white matter. Measurement strategies for neurodegeneration and neuroprotection include clinical parameters, magnetic resonance imaging and novel instruments such as diffusion tensor imaging or optical coherence tomography. Neurotrophic factors activate endogenous neuroprotective pathways. Their up-regulation by CNS-infiltrating immune cells has led to the concept of neuroprotective autoimmunity. The capacity to enhance this endogenous neuroprotection is a valuable property for therapeutic agents and has in detail been studied for glatirameracetate, laquinimod and dimethylfumarate. Multimodal measurement of neuroprotective properties of established and novel MS therapeutics and further elucidation of neuroprotective pathways within the autoimmune process will be useful to augment our insight into the complexity of the disease and to improve therapy, especially in terms of long-term disability and cognitive decline.

Low vitamin D and elevated immunoreactivity against Epstein-Barr virus before first clinical manifestation of multiple sclerosis.

OBJECTIVE: Vitamin D deficiency and Epstein-Barr virus (EBV) infection may be associated with the development of multiple sclerosis (MS). We investigated serum 25-hydroxyvitamin D (25-OH-D) levels and anti-EBV immunoreactivity in 25 individuals before the first clinical manifestation of MS. PATIENTS AND METHODS: 56 serum samples of 25 individuals who had donated blood prior to the first clinical MS manifestation (clinically isolated syndrome (CIS)) (four male subjects, 21 female subjects, mean age 31.5 years at time of pre-CIS blood sampling; mean age at disease onset 33.4 years) were available, covering an interval of 7.3 years-2 months (mean 31.5 months) before CIS. In 18 of 25 patients serum samples were also obtained after established diagnosis of MS. Longitudinal age- and gender-matched healthy blood donors (four male subjects, 21 female subjects, 39 samples, mean age 32.5 years) served as controls. Serum 25-OH-D was measured by isotope dilution-liquid chromatography-tandem mass spectrometry. 25-OH-D levels were deconvoluted using published seasonal coefficients from a German population. Immunoglobulin G (IgG) against Epstein-Barr virus nuclear antigen-1 (EBNA1) were assessed using commercially available ELISA. RESULTS: Low 25-OH-D levels were observed during the 24-month pre-CIS interval (47.8 (32.5-77.2) nmol/l, median (IQR); healthy controls: 81.6 (57.7-98.5), p=0.004, however, still higher than after established diagnosis (24.5 (13.7-47.7), p<0.0001 compared with controls). IgG against EBNA1 during the 36-month pre-CIS interval was increased (185.9 (91.2-460.0) IU/ml, median (IQR); healthy controls 63.7 (29.5-121.6), p=0.002). CONCLUSIONS: Low vitamin D and remote EBV infection may be associated with clinical MS breakthrough within 2-3 years.

Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis.

Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from patients with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in patients with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of patients with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments.

Incidence of therapy-related acute leukaemia in mitoxantrone-treated multiple sclerosis patients in Germany.

BACKGROUND: The incidence of therapy-related acute leukaemia (TRAL) in mitoxantrone treatment in multiple sclerosis (MS) is controversially discussed. METHODS AND RESULTS: In a retrospective meta-analysis from six centres, we observed six cases of acute myeloid leukaemia (AML) (incidence 0.41% for patients with mean follow up after end of treatment of 3.6 years, n = 1.156; incidence 0.25% for all patients, n = 2.261). Potential influencing factors such as myelotoxic or glucocorticosteroid pretreatment/cotreatment were present in all but one case of TRAL. Between 1990 and 2010, 11 cases of TRAL were reported to the Drug Commission of the German Medical Association (estimated risk of 0.09-0.13%). CONCLUSIONS: Regional differences in reported TRAL incidence may point to confounding cofactors such as administration protocols and cotreatments.

Reduced lung function in a chronic asthma model is associated with prolonged inflammation, but independent of peribronchial fibrosis.

BACKGROUND: In asthma, mechanisms contributing to chronicity remain to be determined. Recent models of sensitisation with prolonged airway allergen challenges reproduce typical features of chronic asthma. However, the interplay between inflammation, structural changes and lung function is poorly understood. This study was performed to delineate functional, structural and immunological airway changes after cessation of long term challenges to elucidate factors contributing to the development of prolonged lung function changes. METHODOLOGY/PRINCIPAL FINDINGS: Mice sensitised systemically were consecutively challenged intranasally with ovalbumin for two or eight weeks. After the end of challenges, lung function, airway inflammation, features of airway remodelling, local T-cell cytokines and systemic ovalbumin-specific antibodies were monitored. Long term challenges resulted in airway hyperresponsiveness lasting 2 weeks and reduced baseline lung function for 6 weeks after their cessation. In contrast, these changes resolved within one week after short term challenges. Prolonged transforming growth factor beta (TGF-beta)1 production and marked peribronchial fibrosis were only induced by long term challenges. Importantly, fibrosis became apparent only after the onset of lung function changes and outlasted them. Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response. In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response. CONCLUSIONS: Prolonged lung function changes after long term allergen challenges seem to develop and resolve independently of the persistent peribronchial fibrosis. They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.