H.-P. Hartung

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

BACKGROUND Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING Teva Pharmaceutical Industries, Israel.

MRI evidence of past cerebral microbleeds in a healthy elderly population

Background: Incidental foci of signal loss suggestive of past microbleeds are a frequent finding on gradient-echo T2*-weighted MRI of patients with nontraumatic intracerebral hemorrhage and have been associated with bleeding-prone microangiopathy. If and to what extent such lesions may also occur in the normal population is unclear. Objective: To determine focal hypointensities in asymptomatic elderly individuals and their relation to other clinical and morphologic variables. Methods: T2*-weighted MRI of the brain was performed in a consecutive series of 280 participants (mean age 60 years, range 44 to 79) of the Austrian Stroke Prevention Study. This cohort consisted of randomly selected individuals without history or signs of neuropsychiatric disorder. Results: Past microbleeds ranging from one to five foci of signal loss were seen in 18 (6.4%) individuals. They were strongly associated with higher age, hypertension, and lacunes (p < 0.001), and extensive white matter damage was more frequently noted (p = 0.02). Hypertension was present in all individuals with focal hypointensities in the basal ganglia and infratentorially but in only 5 of 10 volunteers with microbleeds limited to cortico-subcortical sites (p = 0.04). Conclusions: MRI evidence of past microbleeds may be found even in neurologically normal elderly individuals and is related, but not restricted, to other indicators of small vessel disease. The predictive potential of this finding regarding the risk of intracerebral bleeding requires further investigation.

MRI white matter hyperintensities Three-year follow-up of the Austrian Stroke Prevention Study

Objective: To determine the rate, clinical predictors, and cognitive consequences of MRI white matter hyperintensity evolution over 3 years. Methods: In the setting of the Austrian Stroke Prevention Study, 1.5-T MRI was performed at baseline and at a 3-year follow-up in 273 community-dwelling elderly (mean age, 60 ± 6.1 years) without neuropsychiatric disease. At each visit individuals underwent a structured clinical interview and examination, EKG, echocardiography, extensive laboratory workup, and demanding neuropsychological testing. MR images were read by three independent raters, and the change of white matter hyperintensities from baseline was assessed by direct image comparison. The change was graded as absent, minor, or marked. Minor change was defined as a difference of no more than one to four punctate lesions between both scans. A change was considered to be marked if there was a difference of more than four abnormalities or a transition to early-confluent and confluent lesions. Results: Combined ratings indicated lesion progression in 49 individuals (17.9%). Lesion progression was minor in 27 participants (9.9%) and was marked in 22 (8.1%). Regression of white matter hyperintensities did not occur. Diastolic blood pressure (odds ratio, 1.07/mm Hg) and early-confluent or confluent white matter hyperintensities at baseline (odds ratio, 2.62) were the only significant predictors of white matter hyperintensity progression. Lesion progression had no influence on the course of neuropsychological test performance over the observational period. Conclusions: White matter hyperintensities progress in elderly normal subjects. Our data may be used as a reference for future observational and interventional studies on white matter hyperintensity progression in various CNS diseases. The lack of an association between lesion progression and cognitive functioning needs to be explored further.

Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)

Background: Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes. Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative data are not available for all languages and cultures. Objective: To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use. Methods: An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS. Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients. Results: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test – Second Edition and the Brief Visuospatial Memory Test – Revised learning trials if a further 10 minutes could be allocated for testing. Conclusions: A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for language groups and validation studies have commenced.

Statins as immunomodulators Comparison with interferon-β1b in MS

Background Recent data suggest that statins may be potent immunomodulatory agents. In order to evaluate the potential role of statins as immunomodulators in MS, the authors studied their immunologic effects in vitro and compared them to interferon (IFN)&bgr;-1b. Methods Peripheral blood mononuclear cells (PBMC) obtained from untreated or IFN&bgr;-1–treated patients with relapsing-remitting MS or from healthy donors (HD) and T cells were stimulated with concanavalin A, phytohemagglutinin, or antibody to CD3 in the presence of lovastatin, simvastatin, mevastatin, IFN&bgr;-1b, or statins plus IFN&bgr;-1b. The authors analyzed proliferative activity of T cells and B cells, cytokine production and release, activity of matrix metalloproteinases (MMP), and surface expression of activation markers, adhesion molecules, and chemokine receptors on both T and B cells. Results All three statins inhibited proliferation of stimulated PBMC in a dose-dependent manner, with simvastatin being the most potent, followed by lovastatin and mevastatin. IFN&bgr;-1b showed a similar effect; statins and IFN&bgr;-1b together added their inhibitory potentials. Furthermore, statins reduced the expression of activation-induced adhesion molecules on T cells, modified the T helper 1/T helper 2 cytokine balance, reduced MMP-9, and downregulated chemokine receptors on both B and T cells. Besides strong anti-inflammatory properties, statins also exhibited some proinflammatory effects. Conclusions Statins are effective immunomodulators in vitro that merit evaluation as treatment for MS.

Degeneration of retinal layers in multiple sclerosis subtypes quantified by optical coherence tomography.

Background: Optical coherence tomography can be used to assess retinal degeneration in multiple sclerosis (MS). Thinning of the retinal nerve fibre layer and macular thickness have been well characterized, but newer devices allow quantification of all retinal layers. Objectives: The objective of this study was to evaluate the thickness of the paramacular retina, peripapillary retinal nerve fibre layer, and deeper paramacular layers in MS patient subgroups, using state-of-the-art optical coherence tomography. Methods: Using a Heidelberg Engineering Spectralis device, we performed paramacular volumetric retinal scans and circular peripapillary fibre-layer scans, manually segmenting different retinal layers into single horizontal foveal scans in 95 patients with definite MS (42 relapsing–remitting, 41 secondary progressive, 12 primary progressive), plus 91 age- and sex-matched controls. Results: Even without a history of optic neuritis, all MS subgroups had significant thinning of the peripapillary retinal nerve fibre layer, the paramacular retinal thickness and the retinal ganglion cell- and inner plexiform layer. Only in primary progressive MS was the inner nuclear layer significantly reduced. Conclusions: Our findings indicate a primary retinal pathology involving the inner nuclear layer in primary progressive MS. Results in eyes without history of optic neuritis suggest possible subclinical episodes of optic neuritis or retrograde trans-synaptic degeneration of retinal ganglion cells and their axons.

A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS

Objective: To evaluate the efficacy and safety of MBP8298 in subjects with secondary progressive multiple sclerosis (SPMS) who express human leukocyte antigen (HLA) haplotype DR2 or DR4 (DR2+ or DR4+). Methods: This multicenter randomized 2-year, double-blind, placebo-controlled study included 612 subjects with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) score of 3.5–6.5, stratified according to baseline EDSS score (3.5–5.0, or 5.5–6.5) and HLA haplotype (DR2+ or DR4+, or DR2−/DR4−). Upon entry of 100 DR2−/DR4− subjects, further study enrollment was limited to DR2+ or DR4+ subjects. Subjects were randomly assigned to either 500 mg MBP8298 or placebo, given by IV injection once every 6 months for 2 years. The primary outcome measure was time to progression by ≥1.0 EDSS point (or 0.5 point if baseline EDSS was 5.5 or higher), confirmed 6 months later. Secondary outcomes included mean change in EDSS, mean change in Multiple Sclerosis Functional Composite, MRI changes, annualized relapse rate, and quality of life. Results: There were no significant differences between treatment groups in either the primary or secondary endpoints. MBP8298 was well tolerated in all treated subjects with no safety issues identified. Conclusion: In the population studied, treatment with MBP8298 did not provide a clinical benefit compared to placebo. Classification of evidence: This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2+ or DR4+.

Blockade of chemokine signaling in patients with multiple sclerosis

We assessed the safety and efficacy of orally administered CC chemokine receptor 1 (CCR1) antagonist in 105 patients with relapsing/remitting MS (RRMS) in a 16-week, randomized, double-blind, placebo-controlled trial. The primary endpoint was the cumulative number of newly active lesions on serial MRI scans. Other MRI, immunologic, and clinical outcomes were also explored. No significant treatment difference was observed for any tested MRI variable. CCR1 does not contribute to initial leukocyte infiltration in RRMS.

Health-related quality-of-life improvements in CIDP with immune globulin IV 10%: The ICE Study

Background: Chronic inflammatory demyelinating polyradiculoneuropathy trials have demonstrated the efficacy of IV immunoglobulin vs placebo. However, these trails have not addressed the long-term impact on health-related quality of life (HRQoL). Methods: One hundred seventeen patients in a randomized, double-blind, response-conditional crossover trial received immune globulin IV, 10% caprylate/chromatography purified (IGIV-C [Gamunex®]), or placebo every 3 weeks for up to 24 weeks in the first period (FP). Participants whose inflammatory neuropathy cause and treatment disability score did not improve by ≥1 point received alternate treatment in a 24-week crossover period (CP). In either period, participants who improved and completed treatment were eligible to be randomly reassigned to a blinded 24-week extension phase (EP). HRQoL analyses were conducted using the Short Form-36® (SF-36) and the Rotterdam Handicap Scale (RHS). Results: In the FP, greater improvements in both SF-36 physical and mental component scores were observed with IGIV-C vs placebo, with a significant improvement in the physical component score (difference 4.4 points; 95% confidence interval [CI] 0.7–8.0). Improvements in all SF-36 domains favored IGIV-C vs placebo, with physical functioning, role–physical, social functioning, and mental health reaching significance. Participants receiving IGIV-C experienced a larger improvement in RHS vs those receiving placebo (difference 3.4 points; 95% CI 1.4–5.5; p = 0.001). In the CP, similar general trends were observed. In the EP, mean SF-36 improvements were generally improved or maintained in participants who continued IGIV-C therapy; however, worsening was observed in participants re-randomized to placebo. Conclusions: Long-term therapy with immune globulin IV, 10% caprylate/chromatography purified, improves and maintains health-related quality of life in chronic inflammatory demyelinating polyradiculoneuropathy.

Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT

Objective To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). Methods In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 μg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. Results Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms. Conclusions These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS.