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PubMed2006

Interferon-beta1b treatment modulates cytokines in patients with primary progressive multiple sclerosis.

OBJECTIVES: It is unknown whether the immunological effects of beta-interferon (IFN-beta) differ in primary progressive multiple sclerosis (PPMS) when compared with relapsing-remitting multiple sclerosis (RRMS). Therefore, we investigated the effects of IFN-beta1b treatment in PPMS on proliferation and cytokine pattern of peripheral blood mononuclear cells (PBMC) and interleukin-10 (IL-10) serum level. METHODS: Eighteen patients were treated with IFN-beta1b for 12 months in an open-label trial. Serum and PBMC were collected longitudinally. RESULTS: Interleukin-10 serum levels increased (P = 0.02) during treatment. Tumor necrosis factor-alpha was increased in anti CD3 (OKT3) antibody stimulated PBMC during treatment (P = 0.04), whereas secretion of IL-10 was decreased in OKT3 (P = 0.04), but increased in concavalin A stimulated PBMC (P = 0.02). CONCLUSIONS: Interleukin-10 serum levels rose in IFN-beta1b-treated patients as has been observed in RRMS. The changes in cytokine patterns secreted by T-lymphocytes of PPMS patients, however, differ from effects observed in RRMS supporting the hypothesis that PPMS differs in some immunological aspects from RRMS.

Adjuvants, Immunologic↗
PubMed2003

Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12).

OBJECTIVE: To develop a patient-based measure of walking ability in MS. METHODS: Twelve items describing the impact of MS on walking (12-Item MS Walking Scale [MSWS-12]) were generated from 30 patient interviews, expert opinion, and literature review. Preliminary psychometric evaluation (data quality, scaling assumptions, acceptability, reliability, validity) was undertaken in the data generated by 602 people from the MS Society membership database. Further psychometric evaluation (including comprehensive validity assessment, responsiveness, and relative efficiency) was conducted in two hospital-based samples: people with primary progressive MS (PPMS; n = 78) and people with relapses admitted for IV steroid treatment (n = 54). RESULTS: In all samples, missing data were low (< or =3.8%), item test-retest reproducibility was high (> or =0.78), scaling assumptions were satisfied, and reliability was high (> or =0.94). Correlations between the MSWS-12 and other scales were consistent with a priori hypotheses. The MSWS-12 (relative efficiency = 1.0) was more responsive than the Functional Assessment of Multiple Sclerosis mobility scale (0.72), the 36-Item Short Form Health Survey physical functioning scale (0.33), the Expanded Disability Status Scale (0.03), the 25-ft Timed Walk Test (0.44), and Guy's Neurologic Disability Scale lower limb disability item (0.10). CONCLUSIONS: The MSWS-12 satisfies standard criteria as a reliable and valid patient-based measure of the impact of MS on walking. In these samples, the MSWS-12 was more responsive than other walking-based scales.

Adult↗
PubMed2003

Rapid onset mitoxantrone-induced cardiotoxicity in secondary progressive multiple sclerosis.

Mitoxantrone is a recently approved drug for patients with secondary progressive multiple sclerosis (SPMS). However, cardiac side effects limit Mitoxantrone use in SPMS and its lifetime cumulative dose should not exceed 140 mg/m2. Additionally, Mitoxantrone is contraindicated for use in SPMS patients with a baseline left ventricular ejection fraction (LVEF) of < or = 50%. The goal of this study was to monitor LVEF more frequently than ordinarily recommended since experience with Mitoxantrone use in SPMS patients is limited. An unexpected decline in LVEF in one of the SPMS patients being treated with Mitoxantrone prompted further investigation into this finding. In our clinic, 47 patients on Mitoxantrone were followed prospectively; 28 of 47 patients had received a minimum of three doses and underwent a repeat LVEF evaluation prior to their fourth dose of Mitoxantrone. Of these 28 patients, five of 28 (17.8%) had a significant decline in LVEF from baseline. It is suggested that more stringent cardiac monitoring guidelines than current Food and Drug Administration (FDA) recommendations be used to avert potential cardiac complications in SPMS patients on Mitoxantrone.

Adult↗
PubMed2000

Correlation of MRI lesions with visual psychophysical deficit in secondary progressive multiple sclerosis.

The aim of this work was, first, to clarify the nature of the relationship between the sensory deficit in the demyelinated visual pathway and morphological changes revealed by MRI and, secondly, to test whether there was a preferential effect of demyelination for either the magnocellular or parvocellular pathway in established multiple sclerosis. Twenty-four patients with secondary progressive multiple sclerosis were studied psychophysically and by MRI of the optic nerve and brain. MRI was performed with a Phillips (0.5T) scanner. Visual pathway MRI lesion load was evaluated independently using the total optic nerve lesion length and lesion area seen on STIR (short inversion time inversion recovery) images of the optic nerve and the total post-chiasmal lesion area on T(1)-, T(2)- and proton-density-weighted images of the brain. Psychophysical tests determined 75%-seeing thresholds for horizontal gratings consisting of isoluminant red and green sinusoids of the same spatial frequency combined out-of-phase for preferential stimulation of the parvocellular system and in-phase for preferential stimulation of the magnocellular system. It was found that, in this group of patients, visual psychophysical loss was significantly correlated with lesion area seen on proton density MRI sequences of the post-chiasmal visual pathway, and that the parvocellular pathway was more affected than the magnocellular pathway, especially at lower spatial frequencies.

Adolescent↗
PubMed2006

Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.

Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Adult↗
PubMed2002

Cost-utility analysis of interferon beta-1B in secondary progressive multiple sclerosis using natural history disease data.

OBJECTIVES: Different cost-effectiveness analyses have been presented for interferon beta-1b (IFNB) in the treatment of secondary progressive multiple sclerosis (SPMS). All studies have used modeling techniques since any effect on progression of disability achieved during a clinical trial will last beyond the trial. Different approaches to extrapolation have been taken, but generally they have been based on disease progression and relapse rates in clinical trials. The problem with this approach is that the population in clinical trials is a selected group of patients, which has the potential to bias results. A better method for extrapolation is to use epidemiologic data. The objective of this study is to incorporate natural history data for MS into a previously presented cost-utility model and to compare the two methods of extrapolation. METHODS: Clinical trial data were used to model disease progression during the first 3 years in the model. To extrapolate beyond the trial (10 years), data on progression of disability were available from a geographically based epidemiologic study of the natural history of MS in Canada. There were 568 patients who had converted to SPMS during the follow-up that were included in the data set. Mean costs and utilities for each Markov state were calculated from a population-based cross-sectional study in Sweden. RESULTS: The extrapolation using clinical trial data appears to have underestimated the progression of disability in the long term and thus also the potential benefit of treatment. Using the epidemiologic data, the incremental cost per QALY is SEK 257,000 (US $25,700; US $1 = SEK 10; November 2000) when all costs (direct, informal care, and indirect) are included (discounted 3%). This compares to SEK 342,000 in the previous model. The lower cost-effectiveness ratio is mostly due to a larger QALY gain with treatment than in the previous model (0.217 compared with 0.162). CONCLUSIONS: Cost-effectiveness analysis in SPMS requires that the effect of treatment beyond clinical trials be included. The method of extrapolation clearly affects the results, and when available, epidemiologic data should be used. Using the longitudinal data from Canada, the cost-utility ratios for IFNB-1b in the treatment of SPMS appear well within the acceptable range.

Adjuvants, Immunologic↗
PubMedDate not supplied

Mindfulness of movement as a coping strategy in multiple sclerosis. A pilot study.

This study investigated the effectiveness of a short course of mindfulness of movement to help with symptom management in eight people with multiple sclerosis. Progress was compared to a control group who were asked to continue with their current care. Each participant received six individual one-to-one sessions of instruction. They were also provided with audio and videotape aides. Each participant was assessed on a test of balance, pre- and post-intervention, and at 3-month follow-up. All participants completed a rating of change of 22 symptoms relevant to multiple sclerosis. A close relative or friend was also asked to assess independently the degree of change. The mindfulness group reported improvement over a broad range of symptoms. This was verified by the relatives' independent rating and maintained at 3 month follow-up. The control group showed no improvement but instead tended towards a deterioration on many of the items. The physical assessment of balance also showed a significant improvement for the mindfulness group. This improvement was maintained at 3 month follow-up. In conclusion, training in mindfulness of movement appeared to result in improved symptom management for this group of people with multiple sclerosis. This was a pilot study, using small numbers, so the results need to be treated with caution. Several improvements to the experimental design are suggested. The role of individual therapeutic ingredients is discussed.

Activities of Daily Living↗
PubMed2001

In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis.

In patients with primary progressive (PP) multiple sclerosis, brain MRI lesion activity and burden are low, despite the presence of severe neurological impairment. On the contrary, the degree of cord atrophy and diffuse tissue damage in the brain and cervical cord have been found to be associated with clinical disability. Against this background, this study aimed at providing an in vivo indirect assessment of brain and cervical cord pathology in a large cohort of PP multiple sclerosis patients, using conventional MRI and magnetization transfer imaging (MTI). Ninety-one PP multiple sclerosis patients, 36 secondary progressive (SP) multiple sclerosis patients and 30 healthy controls underwent brain and cervical cord MRI scans, using dual echo (brain) or fast short-tau inversion recovery (cervical cord) MTI and T(1)-weighted sequences. For the brain, T(2) hyperintense and T(1) hypointense lesion volumes were calculated and the volume of the whole of the brain tissue measured. For the cervical cord, the number and burden of lesions and the cross-sectional area were assessed. MTI scans were post-processed and analysed to obtain magnetization transfer ratio (MTR) histograms from the whole of the brain and cervical cord tissue and from the normal-appearing brain tissue in isolation. In PP multiple sclerosis patients, brain, normal-appearing brain tissue and cervical cord MTR histogram-derived metrics revealed the presence of diffuse tissue damage whose characteristics did not significantly differ from those of SP multiple sclerosis patients, even though SP multiple sclerosis patients had higher MRI-visible lesion burdens. None of the correlations between MRI or MTI measures obtained from the brain and the cord were significant. PP multiple sclerosis patients' disability was significantly, albeit weakly associated with a composite MR model including measures of loss and intrinsic damage of cervical cord tissue. Our data indicate the presence of a diffuse tissue damage undetectable by conventional MRI in PP multiple sclerosis patients, whose extent seems to match that of SP multiple sclerosis patients with similar levels of disability. They also suggest that the severity of multiple sclerosis pathology in the cervical cord is one of the factors contributing to neurological impairment in PP multiple sclerosis.

Adult↗
PubMed2004

Immunologic factors in primary progressive multiple sclerosis.

Primary progressive multiple sclerosis (PPMS) is clinically characterized by progression without remission or relapse, in contrast to relapsing forms of MS. Pathologic and imaging findings also indicate that PPMS differs from relapsing forms. Recent studies examining potential immunologic differences among MS forms suggest that cytokine and adhesion molecule expression profiles, but not chemokine receptor profiles, in PPMS patients resemble those in healthy controls more than those in patients with relapsing MS. However, the significance of these findings remains to be fully elucidated, and there is little additional evidence as yet of marked differences among MS forms based on immunologic characteristics. Of interest are the recent demonstrations that activated immune cells produce brain-derived neurotrophic factor (BDNF), a neuroprotective factor, in MS lesions, that BDNF receptors are located in MS tissue, and that glatiramer acetate (GA)-specific T cells produce BDNF irrespective of T helper cell Th1 or Th2 phenotype. These findings both support the concept of a protective inflammation in MS and suggest an additional mechanism of action for the clinical effects of GA therapy in MS. Whether and to what extent this mechanism is present in different MS forms remain to be clarified.

Anti-Inflammatory Agents↗
PubMed2006

Anti-GD2-like IgM autoreactivity in multiple sclerosis patients.

Seric IgM autoreactivity in 100 multiple sclerosis (MS) and 106 control (70 of whom had other neurological diseases) patients was assessed either by immunohistochemistry on normal human CNS tissue or to GD2, GD1a, GD3 by ELISA and thin layer chromatography (TLC) techniques. By double immunohistochemistry, we found that 44% of the total MS population showed seric IgM reactivity to oligodendrocytes and myelin, this finding being particularly frequent in patients with secondary progressive MS. In the non-MS cohort, positive signals were seen only in one patient. In all cases, extraction of lipids from CNS sections abolished the immunoreactivity. Among the gangliosides investigated by ELISA, anti-GD2-like IgM autoantibodies were detected in the serum of 30% of MS patients, a subgroup of whom (below 10%) reacted also with GD1a and/or GD3. More than 85% of MS cases with anti-GD2-like IgM immunoreactivity by ELISA showed also IgM antioligodendrocyte/myelin staining by immunohistochemistry. However, no immunostaining in MS sera was observed when gangliosides were resolved by TLC. A positive correlation with neurological disability was observed, as the Expanded Disability Status Scale of MS patients with anti-GD2-like IgM autoreactivity by ELISA was significantly worse than seronegative MS cases. The results of the present study enforce the role of glycolipids as potential autoantigens and of IgM autoantibodies in MS pathogenesis.

Adult↗
PubMed2005

Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis.

Malignant forms of multiple sclerosis (MS) represent a limited group of very aggressive demyelinating diseases, which rapidly progress to severe disability leading often to life-threatening conditions. On these clinical entities, currently available therapies for MS are not very effective. Recently, it has been demonstrated that intense immunosuppression followed by autologous stem cell transplantation (ASCT) can affect the clinical course of individuals with severe MS and completely abrogate the inflammatory activity detected by magnetic resonance imaging (MRI). We report on the treatment with intense immune ablation followed by ASCT of three patients with malignant MS whose clinical course indicated a dramatically poor prognosis. This procedure succeeded in halting the rapidly worsening course of disease. The effect was long lasting, as demonstrated by a sustained efficacy over a two-year period in two subjects and 12 months in the third case. In addition, a striking effect on inflammation-related MRI findings was obtained. These results support a role for intense immunosuppression followed by ASCT as treatment in rapidly evolving malignant MS cases unresponsive to conventional therapies.

Adolescent↗
PubMed2000

A comparison of neuropsychological deficits in primary and secondary progressive multiple sclerosis.

Neuropsychological deficits and the relationship to brain pathology were examined in 13 primary progressive (PP) and 12 secondary progressive (SP) multiple sclerosis patients with a similar duration of the progressive phase and comparable physical disability. A battery of neuropsychological tests to assess attention, short-term and working memory was administered to the patients, and their performance was compared to that of 20 healthy controls matched for age and premorbid IQ. Total cerebral lesion load on T2-weighted magnetic resonance imaging was measured in the patients. Both PP and SP patients performed significantly worse than controls in most of the neuropsychological tests. There were only subtle differences between SP and PP on the working memory task although magnetic resonance imaging lesion load was significantly higher in SP than in PP patients. In this exploratory study only subtle differences in cognitive impairment were detected between SP and PP patients matched for physical disability and relevant illness features. The results also suggest that the severity of cognitive impairment cannot be fully explained by the extent of abnormalities detected on conventional T2-weighted magnetic resonance images, and that other pathological abnormalities such as in normal-appearing white matter are likely to be involved.

Adult↗
PubMed2004

Chromosomal radiosensitivity in secondary-progressive multiple sclerosis patients.

PURPOSE: To investigate chromosomal radiosensitivity of secondary progressive (SP) multiple sclerosis (MS) patients in comparison to a group of healthy individuals. MATERIAL AND METHODS: Chromosomal radiosensitivity was assessed in vitro with the G2 assay and the G0-micronucleus (MN) assay. For the G2 assay phytohaemagglutinin (PHA) stimulated blood cultures were irradiated with a dose of 0.4 Gy 60Co gamma rays in the G2 phase of the cell cycle. For the MN assay unstimulated diluted blood samples were exposed to 3.5 Gy 60Co gamma rays delivered at a high dose-rate (HDR = 1 Gy/min) or low dose-rate (LDR = 4 mGy/min). RESULTS: No significant differences in the number of chromatid breaks were observed between MS patients and healthy individuals. With the G0-MN assay a higher spontaneous MN yield was found in MS patients. At HDR irradiation no significant differences were shown, while at LDR irradiation, MS patients were found less sensitive than healthy controls. The dose-rate sparing index was higher for MS patients, pointing to a better repair capacity. CONCLUSIONS: MS patients are not characterised by an enhanced in vitro chromosomal radiosensitivity. The radioresistant response, which was only observed with the MN assay after LDR irradiation, may point to an adaptive response induced by in vivo oxidative stress in SPMS patients.

Adult↗
PubMed2005

Quantification of cervical cord pathology in primary progressive MS using diffusion tensor MRI.

OBJECTIVE: To investigate the extent and severity of cervical cord damage using diffusion tensor MRI (DT-MRI) and histogram analysis in patients with primary progressive MS (PPMS). METHODS: Diffusion-weighted sensitivity-encoded (SENSE) echoplanar images of the cervical cord and brain dual-echo and diffusion-weighted scans were acquired from 24 patients with PPMS and 13 healthy controls. Cord and brain mean diffusivity and fractional anisotropy histograms were produced. An analysis of variance model, adjusting for cord volume, was used to compare cord DT-MRI parameters from controls and patients. RESULTS: Compared to healthy controls, PPMS patients had reduced cervical cord cross-sectional area and average cord fractional anisotropy (p = 0.007), and increased cord mean diffusivity (p = 0.024). No correlations were found between DT-MRI metrics of the cord and quantities obtained from conventional and DT-MRI of the brain. CONCLUSIONS: DT-MRI of the cervical cord can quantify the extent of diffuse cord pathology in patients with PPMS. Such cord diffusivity changes in patients with PPMS are likely to reflect irreversible axonal injury and reactive gliosis and seem to be independent of brain damage.

Adult↗
PubMedDate not supplied

A phase I study of the safety of honeybee venom extract as a possible treatment for patients with progressive forms of multiple sclerosis.

Although several reports suggest that bee venom may be an effective treatment for patients with multiple sclerosis (MS), patients may be subjected to real risks of serious allergic reactions as well as emotional and economic costs. This study was conducted to evaluate the safety of bee venom extract as a possible treatment for patients with progressive forms of MS. A total of nine bee venom nonallergic patients with progressive forms of MS, who were 21-55 years of age with no other illnesses, were entered into four groups (A, B, C, and D) on a structured 1-year immunization schedule. Hyperreactivity to bee venom was evaluated by questionnaire, physical examination, and a battery of hematologic, metabolic, and immunologic tests. Responses to therapy were evaluated by questionnaire, functional neurological tests, and changes in measurement of somatosensory-evoked potentials. Although no serious adverse allergic reactions were observed in any of the nine subjects, four experienced worsening of neurological symptoms, requiring termination in the study; this could not be ascribed to side effects of the therapy. Of the remaining five subjects, three felt that the therapy had subjective amelioration of symptoms and two showed objective improvement. Although this preliminary study suggests safety, because of the small numbers studied, there were no definite conclusions regarding efficacy and therefore there was little evidence to support the use of honeybee venom in the treatment of MS. Larger and more carefully conducted multicenter studies will be required to establish efficacy.

Adult↗
PubMed2005

Analysis of the human brain in primary progressive multiple sclerosis with mapping of the spatial distributions using 1H MR spectroscopy and diffusion tensor imaging.

Primary progressive multiple sclerosis (ppMS; n=4) patients and controls (n=4) were examined by 1H magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in order to map choline (Cho), creatine and N-acetylaspartate (NAA), the fractional anisotropy (FA) and the apparent diffusion constant (ADC). After chemical shift imaging (point-resolved spectroscopy, repetition time/echo time 1,500 ms/135 ms) of a supraventricular volume of interest of 8x8x2 cm3 (64 voxels) MRS peak areas were matched to the results of DTI for the corresponding volume elements. Mean FA and NAA values were reduced in the ppMS patients (P<0.01, both) and the ADC increased (P<0.02). The spatial distribution of NAA showed strong correlation to ADC in both ppMS patients and controls (r =-0.74 and r= -0.70; P<0.00001, both), and weaker correlations to FA (r=0.49 and r=0.41; P<0.00001, all). FA and ADC also correlated significantly with Cho in patients and controls (P<0.00001, all). The relationship of Cho and NAA to the ADC and the FA and thus to the content of neuronal structures suggests that these metabolite signals essentially originate from axons (NAA) and the myelin sheath (Cho). This is of interest in view of previous reports in which Cho increases were associated with demyelination and the subsequent breakdown of neurons.

Adult↗
PubMed2006

Abnormalities in normal appearing tissues in early primary progressive multiple sclerosis and their relation to disability: a tissue specific magnetisation transfer study.

BACKGROUND: Patients with primary progressive multiple sclerosis (PPMS) often develop severe disability despite low levels of abnormality on conventional magnetic resonance imaging (MRI). This may relate to diffuse pathological processes occurring in normal appearing brain tissue (NABT) involving both white matter (NAWM) and grey matter (NAGM). Magnetisation transfer imaging (MTI) is capable of identifying these processes and may be particularly informative when applied to patients with early PPMS. AIM: To assess the relationship between abnormalities in NABT identified by MTI and disability and other radiological data in patients with early PPMS. METHODS: We studied 43 patients within 5 years of disease onset and 43 controls. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) were scored. Magnetisation transfer ratios (MTR) of NABT, NAWM, and NAGM were calculated and the following MTR parameters were measured: mean, peak height, peak location, and MTR value at the 25th, 50th, and 75th percentiles. Proton density, T2, T1, and gadolinium enhancing lesion loads were also calculated. RESULTS: Differences were found between patients and controls in mean, peak height, and peak location of NAWM and NAGM (p < or = 0.001). Weak to moderate correlations were found between MTR parameters and disability in both NAWM and NAGM. Strong correlations between MTR parameters and lesion loads were found, particularly in NAWM. CONCLUSION: MTR abnormalities are seen in NAWM and NAGM in early PPMS and both are associated with disability. NAWM MTR abnormalities are more closely related to conventional MRI measures than those seen in NAGM.

Adult↗
PubMed2004

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis.

OBJECTIVE: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with secondary progressive MS. METHODS: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. RESULTS: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. CONCLUSIONS: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose-response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

Adjuvants, Immunologic↗