Lack of association between antimyelin antibodies and progression to multiple sclerosis.

BACKGROUND: Patients with a single episode of neurologic dysfunction and brain magnetic resonance imaging (MRI) scans suggestive of multiple sclerosis are at high risk for clinically definite multiple sclerosis, but the outcome for individual patients is unpredictable. An increased risk of progression to clinically definite multiple sclerosis in patients with serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) has been reported. METHODS: We measured serum anti-MOG and anti-MBP IgG and IgM antibodies in 462 patients with a first clinical event suggestive of multiple sclerosis and at least two clinically silent lesions on brain MRI. The patients were participating in a multicenter trial of treatment with interferon beta-1b. Antibodies were assessed by Western blot analysis at baseline, and the results compared with the time and rate of progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis as defined by an international panel (the McDonald criteria). Regular visits were scheduled for the assessment of neurologic impairment and for MRI before treatment and at months 3, 6, 9, 12, 18, and 24. RESULTS: No associations were found between the presence of anti-MOG and anti-MBP IgM and IgG antibodies and progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis according to the McDonald criteria, either in the entire cohort or in any subgroups of the study population. CONCLUSIONS: Serum antibodies against MOG and MBP, as detected by Western blot analysis, are not associated with an increased risk of progression to clinically definite multiple sclerosis in patients who have had a clinically isolated syndrome suggestive of multiple sclerosis.

Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study.

BACKGROUND: Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS. METHODS: In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 microg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211. FINDINGS: Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0.59, 95% CI 0.44-0.80; p=0.0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0.60, 0.39-0.92; p=0.022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0.31). INTERPRETATION: Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b.

BACKGROUND: The BENEFIT study examined interferon beta (IFNB)-1b treatment in patients with clinically isolated syndrome (CIS) and > or = 2 clinically silent brain MRI lesions. METHODS: Subgroups of 468 patients (IFNB-1b: n = 292; placebo: n = 176) were created for demographics, clinical, laboratory, and MRI findings at onset. The 'natural' risk of clinically definite MS (CDMS) over 2 years was estimated by Kaplan Meier statistics in placebo-treated patients; the IFNB-1b treatment effect was analysed by Cox proportional hazards regression. RESULTS: The risk of CDMS was increased in placebo-treated patients (overall 45 %) if they were younger (< 30 years: 60%), were cerebrospinal fluid (CSF)-positive (49 %), or had received steroid treatment (48 %). MRI parameters implied a higher risk in placebo-treated patients with > or = 9 T2-lesions (48%) or > or = 1 gadolinium (Gd)-enhancing lesions (52 %). The CDMS risk was highest (75 %) in placebo-treated patients with monofocal disease onset displaying MRI disease activity (> or = 1 Gd-lesion) and dissemination (> or = 9 T2-lesions). Treatment effects were significant across almost all subgroups including patients with less disease dissemination/activity at onset (monofocal: 55%; < 9 T2-lesions: 60%; no Gd-lesions: 57%) and patients without steroid treatment for the CIS (62 %). Monofocal patients had greater treatment effects if they had > or = 9 T2-lesions (61 %), Gd-lesions (58 %), or both (65 %). CONCLUSIONS: This study confirms the impact of age of onset, CSF and MRI findings on risk of conversion from CIS to CDMS. IFNB-1b treatment effect was robust across the study population including patients without MRI disease activity and less clinical or MRI disease dissemination at onset and patients not receiving steroids for the CIS.

Magnetic resonance imaging effects of interferon beta-1b in the BENEFIT study: integrated 2-year results.

BACKGROUND: In the Betaseron/Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, interferon beta-1b delayed conversion to multiple sclerosis in patients with a first clinical event and at least 2 clinically silent brain magnetic resonance imaging (MRI) lesions. OBJECTIVE: To examine detailed MRI findings from the first 2 years of this trial. DESIGN: Double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 3 study. SETTING: Ninety-eight centers worldwide. PATIENTS: A total of 404 individuals with a first demyelinating event suggestive of multiple sclerosis. INTERVENTIONS: Patients were randomized to receive interferon beta-1b, 250 microg subcutaneously every other day, or placebo. After 24 months of treatment or on conversion to clinically definite multiple sclerosis, open-label interferon beta-1b treatment was offered. MAIN OUTCOME MEASURES: Reported MRI data from patients completing 2 years of follow-up. RESULTS: Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P < .001). This corresponded to lower cumulative numbers of new T2 lesions (median, 1.0 vs 3.0 [reduction of 66%]; P < .001) and new gadolinium-enhancing lesions (median, 0.0 vs 1.0; P < .001) in patients receiving interferon beta-1b vs placebo. From screening to month 24, T2 lesion volume decreased and was more pronounced in patients receiving interferon beta-1b (P = .02). CONCLUSIONS: Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group. Trial Registration clinicaltrials.gov Identifier: NCT00185211.

[Epidemiological model development using BSE as an example--observations from a statistical viewpoint]. / Epidemiologische Modellbildung am Beispiel BSE--Betrachtungen aus statistischer Sicht.

Since first BSE cases in cattle born in Germany were recognized, questions have been raised concerning the future development of the disease and the epidemiological dynamics of BSE, and, consequently, modelling approaches that might answer these questions. The database for such modelling efforts is formed by BSE incidence numbers or incidence rates, broken down by age at onset of clinical disease, and by time of onset or time of birth, respectively, from available information gathered for suspect and confirmed BSE cases. To describe such data, statistical age-period-cohort-models and two epidemiologically/biologically oriented modelling approaches are discussed: the so-called three-factor-model used by the Central Veterinary Laboratory of the British Ministry for Agriculture, Fisheries and Food (MAFF) (now Department of the Environment and Rural Affairs (DEFRA)), and a back-calculation-model developed by a working group at the University of Oxford. Resulting model calculations are supposed to serve several purposes, including a prediction of future BSE incidence numbers, and, especially based on the "Oxford"-model, a back-calculation of the epidemic of BSE infections from the epidemic of clinically diseased BSE cases. Analysis of these approaches reveals some problems even to identify unique age, period, or birth cohort effects. An additional estimation of epidemiological components of BSE, for example the frequency distribution of incubation times, has to rely on further assumptions that cannot be validated by the model fit as such. Therefore, modelling results should be interpreted with caution. However, the limitations demonstrated by this discussion emphasize the need for specific studies to investigate certain aspects of the BSE epidemic, for example the distribution of times from infection to disease onset, and for the centralised collection of valid and detailed population data for cattle.

[Sampling plans and microbiological criteria as risk management options in recently developed food safety concerns]. / Stichprobenpläne und mikrobiologische Kriterien als Risikomanagement-Option in neuen Konzepten zur Lebensmittelsicherheit.

In connection with the World Trade Organization SPS-Agreement new concepts for ensuring food safety have been discussed for some years now. Main topics have been quantitative risk analyses investigating relationships between microbial concentrations in foods and disease probabilities as well as the concept of food safety objectives developed by ICMSF. So far food safety demands have been defined as microbiological criteria. However, usually it is not transparent, whether sampling plans incorporated in such criteria are based on specific prescriptions with regard to decision reliability and tolerable food qualities. In addition, it is still to be discussed, which parts microbiological criteria can play in connection with new concepts of food risk management, for instance as an option to test whether food safety objectives are met or not. The performance of microbiological sampling plans, as visualized by operation characteristic curves, assumptions made in this context, and relationships between food safety objectives and microbiological criteria as well as implications for food safety issues are investigated in this paper.

[Dose-response-models and their implications for quantitative risk assessment for Campylobacter infections]. / Dosis-Wirkungsmodelle und ihre Implikationen im Rahmen einer quantitativen Risikoabschätzung für Campylobacter-Infektionen.

For some time now there have been several projects dealing with the assessment of campylobacteriosis risks for consumers. Dose-response relationships form a crucial part of such assessments, as they specify disease probabilities depending on different microbial concentrations in foods. Evaluation of such models, however, is difficult because of problems to find data on which reliable assumptions could be based. Ongoing risk analyses for Campylobacter mainly refer to a single administration study with human volunteers published by Black et al. (1988). However, whether results from this study can be transferred to target populations envisaged in risk assessments remains questionable for several reasons. In this paper some alternative dose-response models, their fit to the data of Black et al., and risk estimates resulting in a fictitious scenario are discussed and compared. Depending on the dose-response model assumed risk estimates can differ remarkably. Therefore it is hardly possible to make reliable quantifications of risks in reality, however, it can be determined how much they may vary assuming different scenarios.

[Prevalence of herd specific factors and limb disorders, and their associations in intensive swine production]. / Prävalenzen von bestandsspezifischen Faktoren und Gliedmassenerkrankungen, und ihre Assoziationen in der intensiven Schweineproduktion.

A longitudinal observational study in 180 pig breeding herds was performed to calculate prevalences of herd specific factors as well as typical limb disorders and to estimate their associations in a 2-step regression analysis. Regarding herd size, genetics, feeding and weight gain herds were distributed almost equal. The population density and the hygiene status were considered proper in most herds. In the farrowing units partially slatted floors of metal or plastic with slats > 9 mm, in the weaning units fully slatted floors of plastic, and in the rearing units fully slatted floors of concrete were most common. Less than 6% of the farms housed their pigs on solid concrete with straw bedding. Herd prevalences of fault floors varied between 18 and 43%. As a herd health problem (morbidity > 25%) claw hematomas and limb abrasions in just 1-week old piglets, overgrown claws and bursa swellings in weaned pigs, and bursa swellings in rearing pigs were wide spread. Leg deformations by osteopathy or arthritis occurred only sporadically. In the risk analysis claw hematomas of piglets were associated with slatted floors, particulary with slats < 10 mm. Abrasions were associated with concrete and rough floor surfaces at all. Overgrown claws and bursa swellings in weaned and in rearing pigs were associated with damaged, slippery or rough floor surfaces. Other associations were not detected. The quality of floor might be more important than the type of housing.