Genetic susceptibility to multiple sclerosis: interactions between conserved extended haplotypes of the MHC and other susceptibility regions.

BACKGROUND: To study the accumulation of MS-risk resulting from different combinations of MS-associated conserved-extended-haplotypes (CEHs) of the MHC and three non-MHC "risk-haplotypes" nearby genes EOMES, ZFP36L1, and CLEC16A. Many haplotypes are MS-associated despite having population-frequencies exceeding the percentage of genetically-susceptible individuals. The basis of this frequency-disparity requires explanation. METHODS: The SNP-data from the WTCCC was phased at the MHC and three non-MHC susceptibility-regions. CEHs at the MHC were classified into five haplotype-groups: (HLA-DRB1*15:01 ~ DQB1*06:02 ~ a1)-containing (H +); extended-risk (ER); all-protective (AP); neutral (0); and the single-CEH (c1). MS-associations for different "risk-combinations" at the MHC and other non-MHC "risk-loci" and the appropriateness of additive and multiplicative risk-accumulation models were assessed. RESULTS: Different combinations of "risk-haplotypes" produce a final MS-risk closer to additive rather than multiplicative risk-models but neither model was consistent. Thus, (H +)-haplotypes had greater impact when combined with (0)-haplotypes than with (H +)-haplotypes, whereas, (H +)-haplotypes had greater impact when combined with a (c1)-haplotypes than with (0)-haplotypes. Similarly, risk-genotypes (0,H +), (c1,H +), (H + ,H +) and (0,c1) were additive with risks from non-MHC risk-loci, whereas risk-genotypes (ER,H +) and (AP,c1) were unaffected. CONCLUSIONS: Genetic-susceptibility to MS is essential for MS to develop but actually developing MS depends heavily upon both an individual's particular combination of "risk-haplotypes" and how these loci interact.

Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS.

BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

The epidemiology of multiple sclerosis: insights to a causal cascade.

MS-pathogenesis involves both genetic-susceptibility and environmental determinants. Three (or more) sequential environmental-factors are implicated. The first acts near birth, the second acts during childhood/adolescence, and the third acts subsequently. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem particularly well-suited to the first two environmental-events but other factors (e.g., obesity and smoking behavior) seem also to be involved in the causal scheme. MS-pathogenesis can be modeled by incorporating both the environmental and genetic-factors into a causal scheme, which can then help to explain some of the changes in MS-epidemiology (e.g., increasing disease-prevalence, changing sex-ratio, and regional-variations in monozygotic-twin-concordance-rates), which have been taking place recently. This model suggests that genetic-susceptibility is overwhelmingly the most important determinant of MS and that, at least, 92.5% of individuals (and likely much more) are, essentially, incapable of developing MS, regardless of their specific environmental-exposures. Nevertheless, the genetics is complex and the contribution of any specific gene to MS-susceptibility seems to be quite modest. Thus, even for the DRB1*1501 allele (the strongest known MS-susceptibility marker), most carriers are not in the genetically-susceptible group. Moreover, 45-50% of individuals with MS lack this allele entirely and some of the haplotypes that carry this allele don't also confer any disease-risk. Finally, because the prevalence of genetic-susceptibility seems to be so similar throughout North America and Europe, and despite the crucial importance of a person's genetic make-up to disease pathogenesis, it is the environmental-factors, which largely responsible for the observed regional variations in disease-characteristics. Thus, despite MS being more common in women, men are more likely to be genetically-susceptible. This apparent paradox seems to relate to the fact that women are much more responsive than men to the recent changes in environmental-exposure (whatever these have been). These gender-differences may help to explain changes in the sex-ratio and the increasing disease-prevalence, which have both been observed recently. The potential importance of these conclusions regarding the role of environment in MS-pathogenesis is that they open the door to the possibility of pursuing strategies for primary primary disease prevention in the future.

Survival in commercially insured multiple sclerosis patients and comparator subjects in the U.S.

OBJECTIVE: Compare survival in patients with multiple sclerosis (MS) from a U.S. commercial health insurance database with a matched cohort of non-MS subjects. METHODS: 30,402 MS patients and 89,818 non-MS subjects (comparators) in the OptumInsight Research (OIR) database from 1996 to 2009 were included. An MS diagnosis required at least 3 consecutive months of database reporting, with two or more ICD-9 codes of 340 at least 30 days apart, or the combination of 1 ICD-9-340 code and at least 1 MS disease-modifying treatment (DMT) code. Comparators required the absence of ICD-9-340 and DMT codes throughout database reporting. Up to three comparators were matched to each patient for: age in the year of the first relevant code (index year - at least 3 months of reporting in that year were required); sex; region of residence in the index year. Deaths were ascertained from the National Death Index and the Social Security Administration Death Master File. Subjects not identified as deceased were assumed to be alive through the end of 2009. RESULTS: Annual mortality rates were 899/100,000 among MS patients and 446/100,000 among comparators. Standardized mortality ratios compared to the U.S. population were 1.70 and 0.80, respectively. Kaplan-Meier analysis yielded a median survival from birth that was 6 years lower among MS patients than among comparators. CONCLUSIONS: The results show, for the first time in a U.S. population, a survival disadvantage for contemporary MS patients compared to non-MS subjects from the same healthcare system. The 6-year decrement in lifespan parallels a recent report from British Columbia.

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNß-1b trial.

OBJECTIVE: To examine the effects of interferon beta (IFNß)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. METHODS: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNß-1b 250 µg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. RESULTS: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNß-1b 250 µg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNß-1b 250 µg-treated patients (46.0% among IFNß-1b 50 µg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. CONCLUSIONS: There was a significant survival advantage in this cohort of patients receiving early IFNß-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNß-1b benefit on all-cause mortality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that early treatment with IFNß-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Evidence-based guideline update: intraoperative spinal monitoring with somatosensory and transcranial electrical motor evoked potentials: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Clinical Neurophysiology Society.

OBJECTIVE: To evaluate whether spinal cord intraoperative monitoring (IOM) with somatosensory and transcranial electrical motor evoked potentials (EPs) predicts adverse surgical outcomes. METHODS: A panel of experts reviewed the results of a comprehensive literature search and identified published studies relevant to the clinical question. These studies were classified according to the evidence-based methodology of the American Academy of Neurology. Objective outcomes of postoperative onset of paraparesis, paraplegia, and quadriplegia were used because no randomized or masked studies were available. RESULTS AND RECOMMENDATIONS: Four Class I and 8 Class II studies met inclusion criteria for analysis. The 4 Class I studies and 7 of the 8 Class II studies reached significance in showing that paraparesis, paraplegia, and quadriplegia occurred in the IOM patients with EP changes compared with the IOM group without EP changes. All studies were consistent in showing all occurrences of paraparesis, paraplegia, and quadriplegia in the IOM patients with EP changes, with no occurrences of paraparesis, paraplegia, and quadriplegia in patients without EP changes. In the Class I studies, 16%-40% of the IOM patients with EP changes developed postoperative-onset paraparesis, paraplegia, or quadriplegia. IOM is established as effective to predict an increased risk of the adverse outcomes of paraparesis, paraplegia, and quadriplegia in spinal surgery (4 Class I and 7 Class II studies). Surgeons and other members of the operating team should be alerted to the increased risk of severe adverse neurologic outcomes in patients with important IOM changes (Level A).

Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome.

BACKGROUND: Technological advancements in neuroimaging and the increased use of these diagnostic modalities are responsible for the discovery of incidentally identified anomalies within the CNS. In addition to the identification of unanticipated brain MRI abnormalities suggestive of demyelinating disease in patients undergoing neuroimaging for a medical reason other than evaluation for multiple sclerosis (MS), asymptomatic spinal cord lesions are periodically identified. OBJECTIVE: To determine if asymptomatic spinal cord lesions are associated with clinical progression in subjects with radiologically isolated syndrome (RIS). METHODS: A retrospective review of RIS cases at the University of California, San Francisco Multiple Sclerosis Center was performed. The presence of asymptomatic cervical spinal cord MRI lesions was analyzed as a potential predictor for clinical progression. RESULTS: Twenty-five of 71 subjects with RIS possessed findings within the cervical spine that were highly suggestive of demyelinating disease. Of these subjects, 21 (84%) progressed clinically to clinically isolated syndrome (n = 19) or primary progressive multiple sclerosis (n = 2) over a median time of 1.6 years from the date of RIS identification (interquartile range 0.8-3.8). The sensitivity, specificity, and positive predictive value of an asymptomatic spinal cord lesion for subsequent development of either a first demyelinating attack or primary progressive MS were 87.5%, 91.5%, and 84%, respectively. The odds ratio of clinical progression was 75.3 (95% confidence interval 16.1-350.0, p < 0.0001). This association remained significant after adjusting for potential confounders. CONCLUSION: These findings suggest that the presence of asymptomatic spinal cord lesions place subjects with RIS at substantial risk for clinical conversion to either an acute or progressive event, a risk that is independent of brain lesions on MRI.

Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS.

OBJECTIVE: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-beta-1b (IFNbeta-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments. METHODS: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNbeta-1b 50 microg (n = 125), or IFNbeta-1b 250 microg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNbeta-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive. RESULTS: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNbeta-1b treatment, no new adverse events were observed that were associated with long-term IFNbeta-1b exposure. By LTF, NAbs to IFNbeta-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNbeta-1b 50 microg (9/108 [8.3%]) or IFNbeta-1b 250 microg (6/111 [5.4%]). CONCLUSION: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-beta-1b therapy in multiple sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNbeta-1b 50 microg or 250 microg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4-19).

Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial.

BACKGROUND: Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. METHODS: The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutaneously every other day for at least 2 y. Some remained randomised for up to 5 y but, subsequently, patients received treatment according to physicians' discretion. Patients were re-contacted and asked to participate. Efficacy related measures included MRI parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS. RESULTS: Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% (20/109) for placebo versus 8.3% (9/108) for IFNB-1b 50 microg and 5.4% (6/111) for IFNB-1b 250 microg). CONCLUSIONS: The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 microg or 250 microg. The dataset provides important resources to explore early predictors of long-term outcome.

Treatment of early multiple sclerosis: the value of treatment initiation after a first clinical episode.

Multiple sclerosis is a chronic, demyelinating disorder of the central nervous system. It is characterised by progressive neurological disability, which is likely to occur as a result of permanent axonal damage. Such damage may be reflected by brain atrophy, which can be identified early in the course of the disease. Patients who present with an initial episode of inflammatory demyelination, commonly referred to as a clinically isolated syndrome, are at high risk of developing clinically definite multiple sclerosis, especially if their magnetic resonance imaging studies suggest the presence of multi-focal disease. Treatment with disease-modifying therapies at the initial episode of demyelination may postpone this development. In this review we present an overview of evidence supporting early treatment initiation. We focus on three large placebo-controlled trials of interferon beta therapy: Controlled High-Risk Avonex Multiple Sclerosis Prevention Study, Early Treatment of Multiple Sclerosis and Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment. Results from these early treatment studies are presented, and the impact of using interferon beta treatment in the early stages of disease is discussed with the aim of considering optimal therapeutic strategies to improve long-term patient outcome.

Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures.

BACKGROUND: Health-related quality of life (HRQOL) is reduced in multiple sclerosis (MS). It is unclear whether HRQOL is associated with white matter lesion burden or measures of brain atrophy. METHODS: A cross-sectional baseline analysis of 507 patients with MS in a prospective cohort study at the University of California, San Francisco was performed. Multivariate linear regression models were used to determine whether MRI measures were associated with the Emotional Well-Being and Thinking/Fatigue subscale scores of the Functional Assessment in Multiple Sclerosis, a validated HRQOL measure in MS. The difference in each MRI metric associated with a minimal clinically important difference in each HRQOL subscale was calculated. RESULTS: Higher T1 lesion load (15 mL; p = 0.024), normalized T1 lesion volume (20 mL; p = 0.016), or T2 lesion load (25 mL; p = 0.028) was associated with worse scores for Emotional Well-Being. Meaningfully lower scores on this subscale were correlated with lower normalized gray matter volume (118 mL; p = 0.037). Reduced Thinking/Fatigue scores were associated with higher normalized T1 lesion volume (21 mL; p = 0.024), or T2 lesion load (22 mL; p = 0.010) and with lower normalized gray matter (87 mL; p = 0.004), white matter (85 mL; p = 0.025), or brain parenchymal (98 mL; p = 0.001) volume. CONCLUSIONS: Aspects of health-related quality of life (HRQOL) in multiple sclerosis are associated with MRI evidence of white matter lesions and brain atrophy. These findings strengthen the argument for the use of HRQOL outcome measures in trials and suggest that lesion burden on conventional MRI is important for HRQOL.

Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures.

Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via (1)HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm(3); P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention.

Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome.

BACKGROUND: The discovery and broad application of MRI in medicine has led to an increased awareness in the number of patients with incidental white matter pathology in the CNS. Routinely encountered in clinical practice, the natural history or evolution of such individuals with respect to their risk of developing multiple sclerosis (MS) is unclear. OBJECTIVE: To investigate the natural history of patients who exhibit incidental imaging findings highly suggestive of MS pathology. METHODS: Detailed clinical and radiologic data were obtained from asymptomatic patients with MRI anomalies suggestive of MS. RESULTS: The cohort consisted of 41 female and 3 male subjects (median age = 38.5, range: 16.2-67.1). Clinical evaluations were performed in 44 patients at the time of initial imaging; longitudinal clinical follow-up occurred for 30 patients, and longitudinal MRI data were acquired for 41 patients. Neurologic examination at the time of the initial MRI scans was normal in nearly all cases. While radiologic progression was identified in 59% of cases, only 10 patients converted to either clinically isolated syndrome or definite MS. The presence of contrast-enhancing lesions on the initial MRI was predictive of dissemination in time on repeat imaging of the brain (hazard ratio [HR] = 3.4, 95% confidence interval [1.3, 8.7], p = 0.01). CONCLUSION: Individuals with MRI anomalies highly suggestive of demyelinating pathology, not better accounted for by another disease process, are very likely to experience subsequent radiologic or clinical events related to multiple sclerosis. Additional studies will be necessary to fully define this risk.

Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

The clinical and radiologic impact of natalizumab (Tysabri) as therapy for multiple sclerosis (MS) is assessed. On the basis of Class I evidence, natalizumab has been demonstrated to reduce measures of disease activity and to improve measures of disease severity in patients with relapsing-remitting (RR) MS (Level A). The relative efficacy of natalizumab compared to current disease-modifying therapies cannot be defined accurately (Level U). Similarly, the value of natalizumab in the treatment of secondary progressive (SP) MS is unknown (Level U). The value of combination therapy using natalizumab and interferon in the treatment of RRMS is also unknown (Level U). There is an increased risk of developing progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy) and possibly an increased risk of other opportunistic infections (Level C). The PML risk in a pooled clinical trial cohort has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this figure could change in either direction with more experience with the drug.

Neutralizing antibodies to interferon beta-1b are not associated with disease worsening in multiple sclerosis.

The clinical impact of neutralizing antibodies (NAbs) on interferon beta (IFNbeta) efficacy was studied in three large patient cohorts comprising 6698 multiple sclerosis (MS) patients receiving IFNbeta-1b across North America, Europe, and Australia. In North America and Europe, NAb testing was generally undertaken because of a poor clinical response; in Australia, it was mandatory for every patient. Of the 6697 patients tested, 28.9% had at least one NAb titre > or = 20 neutralizing units (NU)/ml, 14.4% had NAb titres > or = 100 NU/ml and 7.7% had NAb titres > or = 400 NU/ml. The NAb-positive rate of 37.0% in Australia was significantly greater than those in North America (21.3%) and Europe (27.6%), and this was observed at every NAb titre level. Our results suggest that NAbs are not responsible for poor clinical responses and that NAb status is of little clinical value. These findings will need to be confirmed in a large independent study.

Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

The clinical and radiologic impact of developing neutralizing antibodies (NAbs) to interferon beta (IFNbeta) while on this therapy for multiple sclerosis (MS) is assessed. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFNbeta (Avonex, Betaseron, or Rebif) is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFNbeta treatment (Level B). In addition, the rate of NAb production is probably less with IFNbeta-1a treatment than with IFNbeta-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in seroprevalence due to variability in the dose of IFNbeta injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFNbeta-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNbeta preparations (either IFNbeta-1a or IFNbeta-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFNbeta treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFNbeta on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply (Level U).

Evidence-based medicine.

Evidence-based medicine (EBM) describes a structured (non-consensus-based) process, in which medical literature is assessed critically to define the value of different therapeutic interventions. Ultimately, the goal is to improve both physician decision making and patient outcome. These assessments begin by defining the specific clinical questions to be answered. Following a structured literature search, evidence that bears on these questions is assembled and classified with respect to the quality of the evidence provided by each study. Lastly, using a set of pre-specified rules, this evidence is translated into specific conclusions and recommendations. Its relative objectivity means that evidence-based medicine can be a powerful tool for practising physicians. As a result, it is important for them to become familiar with this analytical method.

Treatment of multiple sclerosis with human beta interferon.

The present manuscript uses an evidence-based approach to review and analyse evidence for the use of human beta interferon in the treatment of MS. Human beta interferon modulates many of the biological processes believed to be involved in MS development. Beta interferon is a member of a large family of secreted proteins that are involved in an organisms defence against viral infections, cell growth regulation and in modulation of immune response. The therapeutic efficacy of beta interferon in relapsing-remitting and secondary progressive MS has been established in several clinical trials, and evidence indicates that the total weekly dosage of beta interferon and/or the frequency of beta interferon administration are important factors in its clinical use. Future therapeutic developments in MS will be fuelled by our increasing understanding of the physical and biological roles of the interferons, in health and in MS pathogenesis.

Clinical characteristics of African Americans vs Caucasian Americans with multiple sclerosis.

BACKGROUND: African American (AA) individuals are thought to develop multiple sclerosis (MS) less frequently than Caucasian American (CA) individuals. OBJECTIVE: To compare the clinical characteristics of AA and CA patients with MS. METHODS: The clinical features of MS were compared in a large retrospective cohort of AA (n = 375) and CA (n = 427) subjects. RESULTS: The proportion of women to men was similar in AA and CA subjects (81% [AA] vs 77% [CA]; p = 0.122). There were no differences in the proportions of subjects with relapsing-remitting, secondary progressive, primary progressive, and progressive relapsing MS. The median time to diagnosis was 1 year after symptom onset in AA subjects and 2 years after symptom onset in CA subjects (p = 0.0013). The age at onset was approximately 2.5 years later in AA than CA subjects (33.7 vs 31.1 years; p = 0.0001). AA subjects presented with multisite signs and symptoms at disease onset more often than CA subjects (p = 0.018). Clinical involvement restricted to the optic nerves and spinal cord (opticospinal MS) occurred in 16.8% of AA patients compared with 7.9% of CA patients (p < 0.001). Transverse myelitis also occurred more frequently in AA subjects (28 vs 18%; p = 0.001). Survival analysis revealed that AA subjects were at higher risk for development of ambulatory disability than CA subjects. After adjusting for baseline variations and differences in therapeutic interventions, AAs were at 1.67-fold greater risk for requiring a cane to ambulate than CA patients (p < 0.001). There was a trend suggesting that AAs were also at greater risk for development of wheelchair dependency (p = 0.099). Adjusted Cox proportional hazard models showed that this effect was in part attributable to the older age at onset in AAs (p < 0.001). CONCLUSIONS: Compared with multiple sclerosis (MS) in Caucasian Americans, African American patients with MS have a greater likelihood of developing opticospinal MS and transverse myelitis and have a more aggressive disease course.