Barry G. W. Arnason

The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis.

THE INFLAMMATORY LESION IN IDIOPATHIC POLYNEURITIS ARTHUR ASBURY;BARRY ARNASON;RAYMOND ADAMS; Medicine

250 μg or 500 μg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study

BACKGROUND The aim of the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial was to compare the efficacy, safety, and tolerability of 250 microg or 500 microg interferon beta-1b with glatiramer acetate for treating relapsing-remitting multiple sclerosis. METHODS Between November, 2003, and June, 2005, 2447 patients with relapsing-remitting multiple sclerosis were screened and 2244 patients were enrolled in this prospective, multicentre, randomised trial. Patients were randomly assigned 2:2:1 by block randomisation with regional stratification to receive one of two doses of interferon beta-1b (250 microg or 500 microg) subcutaneously every other day or 20 mg glatiramer acetate subcutaneously every day. The primary outcome was relapse risk, defined as new or recurrent neurological symptoms separated by at least 30 days from the preceding event and that lasted at least 24 h. Secondary outcomes were progression on the expanded disability status scale (EDSS) and change in T1-hypointense lesion volume. Clinical outcomes were assessed quarterly for 2.0-3.5 years; MRI was done at screening and annually thereafter. Analysis was by per protocol. This study is registered, number NCT00099502. FINDINGS We found no differences in relapse risk, EDSS progression, T1-hypointense lesion volume, or normalised brain volume among treatment groups. Flu-like symptoms were more common in patients treated with interferon beta-1b (p<0.0001), whereas injection-site reactions were more common in patients treated with glatiramer acetate (p=0.0005). Patient attrition rates were 17% (153 of 888) on 250 microg interferon beta-1b, 26% (227 of 887) on 500 microg interferon beta-1b, and 21% (93 of 445) for glatiramer acetate. INTERPRETATION 500 microg interferon beta-1b was not more effective than the standard 250 microg dose, and both doses had similar clinical effects to glatiramer acetate. Although interferon beta-1b and glatiramer acetate had different adverse event profiles, the overall tolerability to both drugs was similar. FUNDING Bayer HealthCare Pharmaceuticals.

Validation of the Functional Assessment of Multiple Sclerosis quality of life instrument

Based on scientific literature and interviews with clinicians and patients, we developed a quality of life instrument for use with people with MS called the Functional Assessment of Multiple Sclerosis (FAMS).The initial item pool consisted of 88 questions: 28 from the general version of the Functional Assessment of Cancer Therapy quality of life instrument, plus 60 generated by patients, providers, and literature review. The validation samples comprised a mail survey cohort (N = 377) and a clinical cohort (N = 56). Both cohorts provided evidence for internal consistency of the derived subscales, test-retest reliability, content validity, concurrent validity, and construct validity. Principal components and Rasch measurement model analyses were applied sequentially to survey sample data, reducing test length to 44 questions, divided into six subscales: mobility, symptoms, emotional well-being (depression), general contentment, thinking/fatigue, and family/social well-being. Fifteen initially rejected questions were added back as miscellaneous (unscored) questions for their potential clinical and empirical value. The mobility subscale was strongly predictive of the Kurtzke Extended Disability Status Scale and the Scripps Neurologic Rating Scales. The other five subscales were not, indicating they measure aspects of patient quality of life not captured by the neurologic exam. The final 59-item English language instrument (FAMS version 2) is available for inclusion in clinical trials and clinical practice. NEUROLOGY 1996;47: 129-139

Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial

To determine whether glatiramer acetate (GA) slows accumulation of disability in primary progressive multiple sclerosis.

Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis

Interleukin (IL) 1 beta, tumor necrosis factor alpha (TNF alpha), and IL-6 are cytokines which mediate cellular responses during immune activation and inflammation. In multiple sclerosis (MS) they might be responsible for T-cell activation (IL-1 beta), for demyelination (TNF alpha), and for immunoglobulin (Ig) synthesis (IL-6) within the central nervous system. We studied IL-1 beta, TNF alpha, and IL-6 levels in the cerebrospinal fluid (CSF) of 34 patients with MS, 43 patients with non-inflammatory neurological diseases (NIND), and 19 patients with inflammatory neurological diseases (IND). IL-6 was found in the CSF of 29% of MS, 7% of NIND, and 47% of IND patients. TNF alpha was detected in the CSF of 23% of MS, 7% of NIND, and 29% of IND. CSF IL-6 and TNF alpha levels were significantly higher in MS and IND than in NIND. IL-1 beta was rarely detected in the CSF of any group. At least one cytokine was detected in 52% of MS CSF, 11% of NIND CSF, and 64% of IND CSF. In MS patients, no relationship was observed between the incidence or the amount of intrathecal IgG synthesis or oligoclonal bands and the presence of any cytokine. We also evaluated cytokine levels in paired sera from 11 MS and 13 NIND patients. Low levels of IL-6 were detected in most sera from MS and NIND patients. TNF alpha was detected in only two MS sera, and IL-1 beta was undetectable in any sample. Our results indicate that increased CSF levels of the cytokines IL-6 and TNF alpha occur frequently in MS and IND, but there is no obvious relationship to intrathecal Ig synthesis.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

To perform a 1‐stage meta‐analysis of genome‐wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.

Axonal metabolic recovery in multiple sclerosis patients treated with interferon β-1b

Abstract Patients with multiple sclerosis (MS) can benefit from treatment with interferon β–1b. However, the mechanisms of action of this drug are incompletely understood and effects of interferon β–1b on axonal injury are not known. A measure of axonal injury can be obtained in vivo using magnetic resonance spectroscopy to quantify the resonance intensity of the neuronal marker, N-acetylaspartate (NAA). In a small pilot study, we performed combined magnetic resonance imaging and magnetic resonance spectroscopic imaging on 10 patients with relapsing-remitting MS before and 1 year after starting treatment with subcutaneous interferon β–1b. Resonance intensities of NAA relative to creatine (Cr) were measured in a large, central brain volume. These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline. NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5 % 12 months after the start of therapy [2.89 (0.24), p = 0.05], while NAA/Cr in the untreated group decreased, but not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months, p > 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03). Our data suggest that, in addition to losing axons, patients with chronic multiple sclerosis suffer from chronic, sublethal axonal injury that is at least partially reversible with interferon β–1b therapy.

Management of patients receiving interferon beta-1b for multiple sclerosis Report of a consensus conference*

Article abstract-Results of a double-blind, placebo-controlled study in ambulatory patients with relapsing-remitting MS showed that interferon beta-1b reduced the rate of exacerbations by one-third compared with placebo and limited new disease activity in the brain as evidenced by MRI. Interferon beta-1b, administered subcutaneously at a dosage of 0.25 mg (8 million IU) every other day is indicated for the treatment of ambulatory patients with relapsing-remitting MS. Interferon beta-1b may help a wider range of patients, but it should be prescribed only for patients with a diagnosis of clinically definite or laboratory-supported definite MS. The decision to treat a patient with interferon beta-1b should be individualized; that is, based on each patients clinical presentation and course of MS. The most common adverse effects include (1) injection-site reactions and (2) flulike symptoms, which are generally manageable and usually abate after the first few months of treatment. Spasticity may increase. Patients with severe depression or suicidal ideation should be monitored carefully, and symptomatic treatment should be pursued. Interferon beta-1b is contraindicated in pregnant and nursing women. Interferon beta-1b is effective in reducing the progression of total disease burden as seen on MRI in patients with MS. Its use is relatively straightforward and generally does not require alteration in the symptomatic treatment of MS. Patient education and support remain the mainstays of maintaining compliance through the early phases of therapy. NEUROLOGY 1996;46: 12-18

Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon beta-1b

We assessed neuropsychological function longitudinally in 30 MS patients who participated in the pivotal trial of interferon beta-1b (IFN-beta-1b). Nine patients received high-dose IFN-beta-1b (8.0 million units), eight low-dose IFN-beta-1b (1.6 MIU), and 13 placebo. There was significant improvement in Wechsler Memory Scale Visual Reproduction-Delayed Recall scores between years 2 and 4 of the trial in MS subjects receiving high-dose IFN-beta-1b. Motoric performance, MRI lesion area, and depression rating scores did not correlate with this finding. Comparison of MRI at baseline and at years 2 and 4 revealed significant changes over time for the total cohort (p < 0.02). Mean lesion area in the high-dose group did not change over time, whereas the low-dose and placebo groups had increases in total lesion area of 28 and 36%, respectively, at year 4. Expanded disability status scale scores did not change significantly between years 2 and 4 of the trial, nor did they correlate with MRI lesion area at any assessment point. We conclude that high-dose IFN-beta-1b improves delayed visual reproduction test performance in MS patients, a finding unlikely to be explained by practice effects or brain lesion area. NEUROLOGY 1996;47: 1463-1468

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS.