Claudia Gneiss

Smoking is a risk factor for early conversion to clinically definite multiple sclerosis.

Background Cigarette smoking increases the risk for development of multiple sclerosis and modifies the clinical course of the disease. In this study, we determined whether smoking is a risk factor for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome. Methods We included 129 patients with a clinically isolated syndrome, disseminated white-matter lesions on brain magnetic resonance imaging, and positive oligoclonal bands in the cerebrospinal fluid. The patients’ smoking status was obtained at the time of the clinically isolated syndrome. Results During a follow-up time of 36 months, 75% of smokers but only 51% of non-smokers developed clinically definite multiple sclerosis, and smokers had a significantly shorter time interval to their first relapse. The hazard ratio for progression to clinically definite multiple sclerosis was 1.8 (95% confidence interval, 1.2–2.8) for smokers compared with non-smokers (P = 0.008). Conclusions Smoking is associated with an increased risk for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome, and our results suggest that smoking is an independent but modifiable risk factor for disease progression of multiple sclerosis. Therefore, it should be considered in the counseling of patients with a clinically isolated syndrome.

Cerebrospinal fluid B cells correlate with early brain inflammation in multiple sclerosis.

Background There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS). Methodology/Principal Findings In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD138−) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matrix metalloproteinase (MMP)-9 and the B cell chemokine CxCL-13. Conclusions Our data support an important role of CSF B cells in acute brain inflammation in CIS and RRMS.

Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to NAb negativity

Background: It has been reported that in some patients with MS who develop neutralizing antibodies (NAbs) against interferon beta (IFNb), antibody levels can initially increase and then decrease thereafter even when treatment is continued. Objective: To determine whether NAb titre correlates with time to reversion to NAb negativity in patients with multiple sclerosis (MS). Methods: Twenty-eight patients with MS who were NAb-positive during treatment with one of the currently available IFNbs were included in this retrospective study. NAb titres were determined by the myxovirus resistance protein A induction assay. Patients were considered NAb-positive if they had at least two consecutive samples with titres of]/20 neutralizing units (NU). Reversion to NAb-negative status was defined as two consecutive negative samples (NAb titre of B/20 NU) after NAb positivity. Results: When measured two years after treatment initiation, a NAb titre of B/75 NU had a 91.7% sensitivity and a 87.5% specificity for reversion to NAb negativity in the following two years (after a total of four years of treatment). In addition, somewhat surprisingly, patients whose serum converted to NAb-negative generally developed peak NAb titres earlier than patients who remained NAb-positive (mean time of first detection was 21 versus 38 months, respectively). Conclusion: The NAb titre might support treatment decisions in patients with MS whose test results are positive for NAbs.

Increased frequencies of serum antibodies to neurofilament light in patients with primary chronic progressive multiple sclerosis

We investigated whether serum and cerebrospinal fluid (CSF) antibodies to the light subunit of the NF protein (NF-L), a main component of the axonal cytoskeleton, may serve as biological markers for axonal pathology and/or disease progression in multiple sclerosis (MS). IgG to NF-L was measured in sera and CSF of MS patients, patients with inflammatory demyelinating diseases of the PNS, with acute inflammatory neurological diseases (including bacterial and viral meningitis), with neurodegenerative diseases, with acute noninflammatory neurological diseases (including stroke, headache and backache) and healthy controls by enzyme-linked immunosorbent assay. We found that serum anti-NF-L IgG antibodies were significantly elevated in MS patients with primary progressive disease course and we provide evidence for an intrathecal production of these antibodies. Our findings support the use of serum antibodies to NF-L as a marker for axonal destruction.

Plasma levels of soluble adhesion molecules sPECAM-1, sP-selectin and sE-selectin are associated with relapsing-remitting disease course of multiple sclerosis

Adhesion molecule mediated leukocyte migration into the central nervous system is considered to be a critical step in the pathogenesis of multiple sclerosis (MS). We measured plasma levels of the soluble adhesion molecules sPECAM-1, sP-selectin and sE-selectin in 166 MS patients and in 36 healthy blood donors with ELISA. sPECAM-1, sP-selectin and sE-selectin plasma concentrations showed a significant increase in the relapsing-remitting disease course of MS and were elevated during relapse. These findings indicate that sPECAM-1, sP-selectin and sE-selectin might be implemented as paraclinical markers of disease activity in MS with restriction to the clinical course of the disease.

Olfactory threshold is impaired in early, active multiple sclerosis

Background: Olfactory dysfunction has been reported in multiple sclerosis (MS). However, to date no data are available on different qualities of olfactory function, namely odour identification, odour discrimination and odour perception threshold. Objective: To assess different qualities of olfactory function in patients with MS and correlate these with demographic data, clinical data, depression, quality of life and cognitive functions. Methods: In this cross-sectional study, 50 patients with MS or clinically isolated syndrome and 30 healthy controls were included. Olfactory function was measured using the Sniffin’ Sticks test. Results: The scores for odour identification (p = 0.001), odour perception threshold (p = 0.037) and the combined score of odour identification, discrimination and perception threshold (TDI, p = 0.002) were significantly lower in MS. Hyposmia for identification (p = 0.0017), threshold (p = 0.017) and TDI score (p = 0.0014) was more frequent in MS. Olfactory threshold was impaired in patients who were clinically active in the previous year (p = 0.026) and in patients with a disease duration less than 2 years (p = 0.0093). Identification score was negatively correlated with disease duration (p = 0.0017). Olfactory function was not associated with disability, depression or quality of life. Conclusions: We report evidence for qualitatively distinct hyposmia in MS, with increased smell threshold in the early inflammatory phases of the disease and impaired identification with a more widespread chronic disease.

Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients

Interferon beta (IFNβ) is a first-line therapy for multiple sclerosis (MS). However, some patients experience a decline in efficacy with continued therapy due to the development of anti-IFNβ neutralizing antibodies (NAb). We investigated the frequency of NAb cross-sectionally in 846 MS patients who were receiving IFNβ-1b, IFNβ-1a im, or IFNβ-1a sc. The frequency of NAb in patients receiving IFNβ-1a im was lower (5%) than in patients treated with any other form of IFNβ (22-35%) (P < 0.0001). Binding antibodies (BAb) were measured in 808 patients. The frequency differed significantly between treatment groups, ranging from 45% (IFNβ-1a im) to 88% (IFNβ-1b). The proportion of NAb-positive patients within the BAb-positive group differed significantly among treatment groups, ranging between 12% (IFNβ-1a im) and 51% (IFNβ-1a sc). The median NAb titer from all IFNβ-1a-treated patients was higher than from IFNβ-1b-treated patients (446 versus 171 NU/mL, P = 0.04). Among NAb-positive patients, the frequency of NAb titers > 100 NU/mL was 71% for IFNβ-1a compared with 58% for IFNβ-1b (P = 0.04). Except for conflicting data regarding IFNβ-1a sc, the results are generally consistent with the literature and together with the differing proportion of NAb-positive patients within the BAb-positive group, provide further insight into the immunogeni-city of the IFNβ preparations.

Persistency of neutralizing antibodies depends on titer and interferon-beta preparation

Background: Neutralizing antibodies (NAbs) affect the efficacy of interferon-beta (IFNβ) treatment in multiple sclerosis (MS) patients, particularly if NAbs persist. Persistency depends on NAb titers, which differ between IFNβ preparations. Objective: This study evaluated IFNβ preparation-specific NAb cut-off titers during early treatment for prediction of NAb persistency. Methods: Patients who had at least one NAb test between 12 and 30 months (baseline) as well as after more than 48 months (follow-up) on IFNβ treatment were included in this longitudinal study. Results: At baseline 1064 patients had a NAb test. Of those, 203 had a follow-up test. In the follow-up group 23.2% of patients were NAb positive during baseline. NAb frequency significantly decreased by 40.7% in the IFNβ-1a and by 60% in the IFNβ-1b group at follow-up after a mean time of 75.4 months on treatment, and median NAb titers decreased significantly in both groups. During baseline, NAb titers of >258 neutralizing units (NU) had a sensitivity of 81.3% and a specificity of 90.9% in the IFNβ-1a group, whereas titers of >460 NU had a sensitivity of 100% and a specificity of 91.7% in the IFNβ-1b group to predict persistency at follow-up. When these cut-off titers are applied, 10.2% of all treated patients developed persistent NAbs. Conclusion: IFNβ preparation-specific NAb cut-off titers for prediction of NAb persistency, which may be useful in individual treatment decision making, are provided.

Natalizumab treatment reduces endothelial activity in MS patients.

Vascular cell adhesion molecule-1 a ligand for leukocyte very late activating antigen-4 is a key player in leukocyte extravasation in MS lesions. Natalizumab a monoclonal antibody against VLA-4 blocks this interaction. VCAM-1 and its soluble form are up-regulated during endothelial activation in MS. We investigated the effect of Natalizumab on sVCAM-1 and VLA-4 on circulating leukocytes in MS patients. Natalizumab reduced levels of sVCAM-1 compared to controls (256 vs. 597 ng/mL). This effect was sustained and only reversed in patients with neutralizing antibodies against Natalizumab. Correspondingly Natalizumab diminished VLA-4 on leukocyte subsets. Our findings indicate that Natalizumab reduces transmigration not only by blocking VLA-4 but also by down-regulating VCAM-1.

Epitope Specificity of Neutralizing Antibodies Against IFN-β

Neutralizing antibodies (NAb), a subset of antibodies against interferon-β (IFN-β) that inhibit activation of the IFN-β receptor, are presumed to bind to the receptor-binding site of IFN-β. The aim of this study was to identify specific epitopes for human NAb and nonneutralizing antibodies (NNAb) on the IFN-β molecule. Thirty-one 12-mer peptides and one 11-mer peptide representing the amino acid sequence of the human IFN-β molecule were used as antigens in an ELISA antibody assay. Significant antibody binding was observed at residues 1-12, 121-132, and 151-162. NNAb and NAb recognized residues 121-132 with equal frequency, but NAb had higher titers. NAb bound significantly more frequently to residues 1-12 and 151-162. There was a significant positive correlation between NAb titers and titers against residues 1-12. Binding to residues 1-12 was more pronounced in patients treated with IFN-β1a than in patients treated with IFN-β1b. Our results indicate a qualitative and quantitative difference between NAb an...