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.

MxA protein--an interferon beta biomarker in primary progressive multiple sclerosis patients.

BACKGROUND AND PURPOSE: Interferon beta (IFNbeta) preparations have some effect on the progressive phase of multiple sclerosis (MS). This limited effect might be partially because of a certain number of IFNbeta non-responders. Myxovirus resistance protein A (MxA)--a marker of IFNbeta bioactivity--was correlated with the clinical response during an uncontrolled trial, investigating the safety of IFNbeta-1b in primary progressive (PPMS) patients. METHODS: Twenty PPMS were treated with IFNbeta-1b (s.c.) for 1 year. Blood samples were taken before and 1, 2, 3, 6, 9, 12, and 15 months after treatment initiation and MxA protein levels were measured. Patients were clinically evaluated by EDSS and the more sensitive Incapacity Status Scale (ISS) and stratified in a stable and a progressing group. RESULTS: Using ISS criteria, 11 patients remained stable and nine patients progressed during treatment. The mean area under the curve of log MxA levels during treatment were significantly higher in stable than in progressing patients (10.87 vs. 5.99; P = 0.002). CONCLUSION: A good biological response to IFNbeta might be associated with a better clinical effect of this drug and could be helpful in future clinical studies for early identification of treatment responders.

Interferon-beta antibodies have a higher affinity in patients with neutralizing antibodies compared to patients with non-neutralizing antibodies.

In this study, we investigated the affinity, determined by a relative affinity assay, using increasing concentrations of sodium-isothiocyanate to disrupt the antigen antibody binding of neutralizing and non-neutralizing antibodies against interferon-beta (IFNbeta)-1a and -1b in 73 serum samples of MS patients treated with IFNbeta-1a or -1b. Relative affinity values were significantly higher in NAB-positive compared to NAB-negative samples and in samples of IFNbeta-1a-treated patients compared to IFNbeta-1b. A significant positive correlation between relative affinity values and therapy duration indicates affinity maturation as another qualitative factor in IFNbeta neutralization.

High-dose intravenous interferon beta in patients with neutralizing antibodies (HINABS): a pilot study.

BACKGROUND: Neutralizing antibodies (NABs) against interferon beta (IFNbeta) are associated with a loss of IFNbeta bioactivity and clinical effectiveness. To date, there are no anti-NAB strategies available. The primary objective of this trial was to investigate whether intravenous IFNbeta-1b can restore bioactivity in NAB-positive patients with MS. METHODS: NAB-positive patients with MS were treated with 8 MIU IFNbeta-1b s.c., 8 MIU i.v., and 16 MIU i.v. Each application was preceded by a wash-out period of 1 week. Blood samples were collected before, 3, 12, and 24 h after each administration. Myxovirus protein A (MxA) RNA and protein levels were determined. The study has been approved by the local ethics committee. RESULTS: Five patients completed the study. NAB titers ranged from 42 to 4482 neutralizing units. Median MxA protein (1821, range 12-3234) and RNA (2186, range 114-7525) area under the curve levels for the four measurements at each IFNbeta injection were significantly higher after i.v. application of 16 MIU as compared with both 8-MIU dosages, which were 743 (0-2709) for MxA protein after 8 MIU i.v. and 254 (0-1200) after s.c., and 1763 (25-7188) for MxA RNA after 8 MIU i.v., and 557 (5-2265) after s.c. applications. NAB titers decreased significantly and transiently after infusion of 16 MIU IFNbeta-1b but not after both forms of 8 MIU applications. Typical side effects could be controlled by paracetamol. No allergic reaction was observed. DISCUSSION: The results indicate that i.v. administration of IFNbeta can restore bioavailability of IFNbeta in patients with NABs.

Comparative study of four different assays for the detection of binding antibodies against interferon-beta.

BACKGROUND: Binding antibodies (BAB) against interferon-beta (IFNbeta) are often determined as screening assays before performing an expensive and elaborate neutralizing antibody (NAB) test. METHODS: In this study, we compared four BAB tests, a western blot (WB), a direct binding enzyme-linked immunosorbent assay (ELISA) (dELISA), a capture ELISA (cELISA), and a commercial enzyme immuno-assay (EIA) in 325 multiple sclerosis patients with and without neutralizing antibodies to evaluate the sensitivity and specificity to detect NAB by receiver operating characteristics analysis. RESULTS: The area under the curve (AUC) values were 0.907 for the dELISA, 0.925 for the cELISA, and 0.776 for the EIA (P < 0.0001 for all). At a sensitivity of 95%, the specificity was approximately 30% in the dELISA, 55% in the cELISA, and 13% in the EIA. The WB as a qualitative BAB detection method had a given sensitivity of 97% and a specificity of 55%. There was a strong and significant correlation between high NAB titers (>500 neutralizing units [NU]) and titers obtained by all quantitative BAB assays. However, low to medium NAB titers (20-500 NU) did not significantly correlate with BAB titers. CONCLUSION: We conclude that the cELISA seems to be most suitable for NAB screening, but BAB titers cannot reliably predict NAB titers.

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.

Differing immunogenic potentials of interferon beta preparations in multiple sclerosis patients.

Interferon beta (IFNbeta) 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-IFNbeta neutralizing antibodies (NAb). We investigated the frequency of NAb cross-sectionally in 846 MS patients who were receiving IFNbeta-1b, IFNbeta-1a im, or IFNbeta-1a sc. The frequency of NAb in patients receiving IFNbeta-1a im was lower (5%) than in patients treated with any other form of IFNbeta (22-35%) (P < 0.0001). Binding antibodies (BAb) were measured in 808 patients. The frequency differed significantly between treatment groups, ranging from 45% (IFNbeta-1a im) to 88% (IFNbeta-1b). The proportion of NAb-positive patients within the BAb-positive group differed significantly among treatment groups, ranging between 12% (IFNbeta-1a im) and 51% (IFNbeta-1a sc). The median NAb titer from all IFNbeta-1a-treated patients was higher than from IFNbeta-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 IFNbeta-1a compared with 58% for IFNbeta-1b (P = 0.04). Except for conflicting data regarding IFNbeta-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 immunogenicity of the IFNbeta preparations.

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.

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 (IFNbeta), 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 IFNbetas 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 > or = 20 neutralizing units (NU). Reversion to NAb-negative status was defined as two consecutive negative samples (NAb titre of < 20 NU) after NAb positivity. RESULTS: When measured two years after treatment initiation, a NAb titre of < 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.