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 µg 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 µg 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 µg 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

Prognostic factors for long-term outcomes in relapsing-remitting multiple sclerosis

Objective: The objective of this article is to investigate potential clinical and MRI predictors of long-term outcomes in multiple sclerosis (MS). Methods: This was a post hoc analysis using data from all 382 patients in the PRISMS long-term follow-up (LTFU) study collected up to eight years after randomisation. An additional analysis was performed including only those patients originally randomised to receive early subcutaneous interferon (IFN) β-1a (n = 259). Baseline/prestudy variables, indicators of early clinical and MRI activity (baseline to month 24), and indicators of IFN β-1a treatment exposure (including medication possession ratio (MPR)) were investigated as candidate prognostic factors for outcomes measured from baseline and from month 24 to LTFU. Explanatory variables identified from univariate regression models (p ≤ 0.15) were selected for inclusion in stepwise multiple regression models. Results: Candidate prognostic factors selected by the univariate analysis (p ≤ 0.15) included age, MS duration, baseline brain volume, EDSS score, and log(T2 burden of disease (BOD)). In most of the multivariate regression models applied, higher baseline brain volume and MPR predicted better long-term clinical outcomes, while higher baseline and greater early increase in EDSS score predicted worse outcomes. Conclusion: Identification of markers that may be prognostic for long-term disability could help identify MS patients at higher risk of disability progression

NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial

Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce the yearly relapse rate in patients with relapsing-remitting multiple sclerosis. Methods: NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) was a randomised, placebo-controlled trial done in 29 neurology departments in Denmark, Norway, Sweden, and Finland. We enrolled outpatients with relapsing-remitting multiple sclerosis who had had at least one relapse within the previous 12 months despite subcutaneous interferon beta-1a treatment (44 microg three times per week). We randomly allocated patients by computer to add-on therapy of either 200 mg methylprednisolone or matching placebo, both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary outcome measure was mean yearly relapse rate. Primary analyses were by intention to treat. This trial is registered, number ISRCTN16202527. Findings: 66 patients were assigned to interferon beta and oral methylprednisolone and 64 were assigned to interferon beta and placebo. A high proportion of patients withdrew from the study before week 96 (26% [17 of 66] on methylprednisolone vs 17% [11 of 64] on placebo). The mean yearly relapse rate was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; p<0.0001). Sleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks. Interpretation: Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis leads to a significant reduction in relapse rate. However, because of the small number of patients and the high dropout rate, these findings need to be corroborated in larger cohorts

Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria

New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 201

Are Cerebrospinal Fluid Biomarkers Useful in Predicting the Prognosis of Multiple Sclerosis Patients?

Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disorder of the central nervous system (CNS). Although many advances have been made in the comprehension of its pathogenesis, the etiology is still unknown. The complexity of MS reflects in the extreme variability of the clinical manifestations and clinical course both between and within patients, in addition to immunopathological mechanisms and response to treatment. Several prognostic factors have been suggested in large scale studies, but predictions in individual cases are difficult to make. Cerebrospinal fluid (CSF) biomarkers, such as 14-3-3, tau, and cystatin C are promising sources of prognostic information with a good potential of quantitative measure, sensitivity, and reliability. However, none has shown sufficient reproducibility to be applied in clinical practice. Here we review the current literature addressing the above mentioned biomarkers as MS severity predictors at an early stage

Effectiveness of temozolomide for primary glioblastoma multiforme in routine clinical practice

Temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiforme since 2005. To assess the effectiveness of temozolomide in routine clinical practice, we conducted an observational study at Maastricht University Medical Centre (MUMC). Data of patients receiving radiotherapy and temozolomide between January 2005 and January 2008 were retrieved from a clinical database (radiochemotherapy group), as were data of patients in a historical control group from the period before 2005 treated with radiotherapy only (radiotherapy group). The primary endpoint was overall survival. A total of 125 patients with GBM were selected to form the study cohort. Median survival benefit was 4 months: the median overall survival was 12 months (95% CI, 9.7–14.3) in the group with radiochemotherapy with temozolomide, versus 8 months (95% CI, 5.3–10.7) in the group with only radiotherapy. Progression-free survival was 7 months (95% CI, 5.5–8.5) in the radiochemotherapy group and 4 months (95% CI, 2.9-5.1) in the group with only radiotherapy. The two-year survival rate was 18% with radiochemotherapy with temozolomide against 4% with radiotherapy alone. Concomitant treatment with radiotherapy and temozolomide followed by adjuvant temozolomide resulted in grade III or IV haematological toxic effects in 9% of patients. The addition of temozolomide to radiotherapy in routine clinical practice for newly diagnosed glioblastoma resulted in a clinically meaningful survival benefit with minimal haematological toxicity, which confirms the experience of previous trials and justifies the continued use of temozolomide in routine clinical practice

On cerebrospinal fluid immunoglobulin-G (IgG) quotients in multiple sclerosis and other diseases : A review and a new formula to estimate the amount of IgG synthesized per day by the central nervous system

This review of the cerebrospinal fluid (CSF) changes in multiple sclerosis has brought together relevant recent advances in CSF physiology and some aspects of the pathology of MS as they relate to the CSF IgG quotients.A defense of the hypothesis that an elevated CSF IgG value in MS is the result of a basic mechanism of the CNS which does not operate normally, i.e., that IgG diffuses through the ECS of the CNS into the CSF from sites of synthesis of IgG in the CNS, but it is contained inside the blood-CNS-CSF barrier which is only accasionally slightly abnormal is presented. It is proposed that this basic mechanism underlies the elevated CSF IgG quotients (IgG/total protein and IgG/albumin); other diseases which induce the CNS to become an immunological organ, i.e., to produce IgG, are clinically infrequent and are easily differentiated on clinical grounds from MS; thus the elevated CSF IgG quotient found in over two-thirds of the cases of MS becomes of value in supporting the diagnosis of MS.Finally, a formula is presented which estimates the amount of IgG, expressed in mg, which is synthesized per day by the MS CNS. The average amount synthesized per day by a MS patient is 16 mg with a range of 0-100 mg.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32790/1/0000163.pd