Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database.

BACKGROUND: Appropriate counseling and treatment for women with multiple sclerosis (MS) who may become pregnant requires an understanding of the effects of exposure to disease-modifying therapies (DMTs) during pregnancy. Current reports and studies are limited in their usefulness, mostly by small sample size. Branded glatiramer acetate (GA) is a DMT approved for the treatment of relapsing forms of MS. For more than 2 decades, it has been shown to be efficacious and to have a favorable safety profile. The Teva Pharmaceutical Industries Ltd global pharmacovigilance database comprises data from more than 7000 pregnancies, during which women with MS were exposed to treatment with branded GA. METHODS: We analyzed data from Teva's global pharmacovigilance database. Pregnancy outcomes for patients treated with branded GA were compared with reference rates of abnormal pregnancy outcomes reported in two large registries representing the general population. RESULTS: Pregnancies exposed to branded GA were not at higher risk for congenital anomalies than what is expected in the general population. CONCLUSIONS: These data provide evidence that branded GA exposure during pregnancy seems safe, without teratogenic effect.

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) ß-1a (n = 259). Baseline/prestudy variables, indicators of early clinical and MRI activity (baseline to month 24), and indicators of IFN ß-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.

The risk of malignancy is not increased in patients with multiple sclerosis treated with subcutaneous interferon beta-la: analysis of data from clinical trial and post-marketing surveillance settings.

BACKGROUND: Risks that are potentially associated with long-term therapies should be assessed. OBJECTIVE: The present analyses were performed to determine the risk of malignancy in patients with multiple sclerosis (MS) receiving subcutaneous (sc) interferon (IFN) beta-1a, using pooled safety data from key clinical trials and data from the Merck Serono Global Drug Safety database. METHODS: The standard Medical Dictionary for Regulatory Activities query "malignancies" was used to retrieve relevant cases from each data set. The incidence of malignancies per 1000 patient-years was calculated using the pooled safety data from clinical trials. The reporting rates of malignancy types were calculated for the post-marketing setting based on sales volume. Malignancies were grouped by organ localization and classified as medically confirmed or not medically confirmed according to the source of each report. The number of reported cases of each type was compared with the expected number in the general population. RESULTS: Analysis of pooled safety data from 12 key clinical trials did not show an increased incidence of malignancy per 1000 patient-years with sc IFN beta-1a (4.0; 95% confidence interval (CI): 2.9-5.5) compared with placebo (6.4; 95% CI: 3.3-11.2). Analysis of the database shows that among the medically confirmed cases, reported to expected ratios ranged from 1 : 6 to 1 : 18 for solid tumours and from 1 : 2 to 1 : 9 for lymphohaematopoietic tumours. CONCLUSION: Safety data from both clinical trial and post-marketing settings suggest that treatment with sc IFN beta-1a does not increase the risk of malignancy in patients with MS.

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.

Impact of exposure to interferon beta-1a on outcomes in patients with relapsing-remitting multiple sclerosis: exploratory analyses from the PRISMS long-term follow-up study.

OBJECTIVE: To explore the effects of exposure to subcutaneous (sc) interferon (IFN) beta-1a on efficacy in patients with relapsing-remitting multiple sclerosis (RRMS) enrolled in the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study. METHODS: Patients with RRMS received IFN beta-1a, 44 or 22 µg sc three times weekly (tiw), or placebo, for 2 years, at which point placebo recipients were re-randomized to IFN beta-1a, 44 or 22 µg sc tiw, for a further 2-4 years. Long-term follow-up visits occurred 7-8 years after enrolment and allowed participation of patients who had previously discontinued treatment. Post hoc descriptive analyses were conducted within the lower (MIN) and upper (MAX) quartiles of patients divided according to cumulative dose of IFN beta-1a and cumulative time on treatment. Outcomes were explored in patients initially randomized to IFN beta-1a, 44 µg sc tiw, who had received continuous or noncontinuous therapy during the study. RESULTS: For both cumulative dose and time analyses, the MIN and MAX groups comprised 96 and 95 patients, respectively. The continuous and noncontinuous groups included 45 and 91 patients, respectively. The MAX DOSE and MAX TIME groups had lower annualized relapse rates, lower rates of conversion to secondary progressive MS, lower percentages of patients with Expanded Disability Status Scale progression, higher percentages of relapse-free patients, and less T2 burden of disease than the MIN groups. The continuous therapy group had a lower annualized relapse rate and lower percentages of patients with Expanded Disability Status Scale progression or conversion to secondary progressive MS than the noncontinuous therapy group. CONCLUSIONS: The findings of these post hoc analyses suggest that high exposure to sc IFN beta-1a may be associated with better clinical outcomes than low exposure, and also highlight the importance of maximizing adherence. Additional prospective investigation is warranted to evaluate further the effects of treatment exposure on outcomes and to determine the benefits of interventions to improve adherence.

Pregnancy outcomes in multiple sclerosis following subcutaneous interferon beta-1a therapy.

BACKGROUND: Women with multiple sclerosis (MS) are advised to discontinue interferon-beta therapy before trying to conceive. Unplanned pregnancies occur and risks related to exposure remain unclear. METHODS: To determine pregnancy outcomes following interferon-beta therapy, we examined pregnancies from a global drug safety database containing individual case safety reports received in the post-marketing setting and safety data from clinical trials of subcutaneous interferon beta-1a in MS. RESULTS: One thousand and twenty-two cases of exposure to subcutaneous interferon beta-1a during pregnancy were retrieved; 679 had a documented outcome. In cases for which exposure duration was available (n = 231), mean time of foetal exposure to subcutaneous interferon beta-1a before treatment discontinuation was 28 days; most pregnancies (199/231; 86.1%) were exposed for ≤ 45 days. To avoid bias, only outcomes for prospective data (n = 425) in pregnancies exposed to interferon beta-1a in utero were analysed further. Of these, 324 (76.2%) resulted in normal live births and four (0.9%) in live births with congenital anomalies (3 [0.7%] were 'major'). Four (0.9%) pregnancies resulted in stillbirths (1 [0.2%] with foetal defects). There were 5 (1.2%) ectopic pregnancies, 49 (11.5%) spontaneous abortions and 39 (9.2%) elective terminations. Most pregnancies exposed to subcutaneous interferon beta-1a in utero were associated with normal live births. The rates of spontaneous abortion and major congenital anomalies in live births were in line with those observed in the general population. CONCLUSIONS: These data should be taken into account when considering options for women with MS who become pregnant or who are planning pregnancy while on treatment with subcutaneous interferon beta-1a.

Recognizing and treating suboptimally controlled multiple sclerosis: steps toward regaining command.

OBJECTIVE: The therapies available today for multiple sclerosis (MS) reduce but do not fully control disease activity. The objective of this article is to review the definitions of and treatments for suboptimally controlled MS and highlight the challenges faced by clinicians to increase awareness of recognizing and managing patients with suboptimally controlled MS. METHODS: Published literature describing treatment failure, treatment optimization paradigms or algorithms, clinical studies of therapies in patients with suboptimally controlled MS, or case reports of management of patients with suboptimally controlled MS were identified from searches of EMBASE and MEDLINE. This was supplemented with case reports and discussions from an expert panel meeting of MS specialists focused on the diagnosis and treatment of suboptimally controlled MS. RESULTS: Several groups have created recommendations for evaluating suboptimal response to disease-modifying drugs (DMDs) in MS. Currently no robust evidence-based data exist to guide treatment decisions in patients who have suboptimal response to a particular therapy. In the absence of data, several treatment paradigms for suboptimally controlled MS have been proposed using a step therapy or platform therapy approach. Therapy modifications require consideration of disease- and patient-specific factors while accounting for the risk-benefit profile of the agent(s). Unapproved drugs and combination therapies should be reserved as agents of last resort because of the experimental nature of these treatments. CONCLUSIONS: In the absence of evidence-based data, identifying and treating MS patients with suboptimal response to the available platform therapies remains challenging. Developing algorithms able to quantify breakthrough disease activity and suboptimal response to DMDs in individual MS patients remains an important target for the MS community. Consideration should be given for all reasons why a particular DMD may not be working for a given patient and for the use of an individualized step therapy.

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.

BACKGROUND: 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: 2005 revisions to the "McDonald Criteria".

New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Enhanced benefit of increasing interferon beta-1a dose and frequency in relapsing multiple sclerosis: the EVIDENCE Study.

BACKGROUND: The EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study demonstrated that patients with multiple sclerosis (MS) who initiate interferon beta-1a therapy with 44 microg 3 times weekly (TIW) were less likely to have a relapse or activity on magnetic resonance imaging (MRI) compared with those who initiate therapy at a dosage of 30 microg 1 time weekly (QW). OBJECTIVE: To determine the effect of changing the dosage from 30 microg QW to 44 microg TIW in this extension of the EVIDENCE Study. DESIGN/PATIENTS: Patients with relapsing MS originally randomized to interferon beta-1a, 30 microg QW, during the comparative phase of the study changed to 44 microg TIW, whereas patients originally randomized to 44 microg TIW continued that regimen. Patients were followed up, on average, for an additional 32 weeks. MAIN OUTCOME MEASURE: The within-patient pretransition to post-transition change in relapse rate. RESULTS: At the transition visit, 223 (73%) of 306 patients receiving 30 microg QW converted to 44 microg TIW, and 272 (91%) of 299 receiving 44-microg TIW continued the same therapy. The post-transition annualized relapse rate decreased from 0.64 to 0.32 for patients increasing the dose (P<.001) and from 0.46 to 0.34 for patients continuing 44-microg TIW (P = .03). The change was greater in those increasing dose and frequency (P = .047). Patients converting to the 44-mug TIW regimen had fewer active lesions on T2-weighted MRI compared with before the transition (P = .02), whereas those continuing the 44-microg TIW regimen had no significant change in T2 active lesions. Patients who converted to high-dose/high-frequency interferon beta-1a therapy had increased rates of adverse events and treatment terminations consistent with the initiation of high-dose subcutaneous interferon therapy. CONCLUSIONS: Patients receiving interferon beta-1a improved on clinical and MRI disease measures when they changed from 30 microg QW to 44 microg TIW.

Interferon-beta1a treatment for multiple sclerosis.

Although multiple sclerosis is probably the most common cause of neurologic disability in young adults, the cause is unknown, the prognosis uncertain and available treatments unsatisfactory. Multiple sclerosis is an inflammatory autoimmune disorder of the CNS and the result of both environmental factors and susceptibility genes. The prognosis is difficult or impossible to predict at the time of diagnosis. Treatments that modulate the course of the disease have only recently become available but the long-term aim to prevent disability and promote repair remains distant. Interferon-beta is the most widely used therapy. The efficacy of interferon-beta in the short term is well documented in many large treatment trials, but the treatment effects are only modest and many issues relating to efficacy in the long term are unresolved. These include uncertain benefit on conversion to secondary-progressive multiple sclerosis, the relevance of neutralizing antibodies and the controversial effect on multiple sclerosis-related brain atrophy.

Predicting the outcome of optic neuritis: evaluation of risk factors after 30 years of follow-up.

BACKGROUND: Multiple sclerosis (MS) is a common disease with considerable risk for disability. Optic neuritis (ON) is a common first symptom of MS but it can also remain an isolated episode. Therefore, predicting the outcome of ON has gained in importance, particularly in light of current discussions of early disease modifying treatments in individuals at risk of developing MS. We reported previously on our cohort of 86 patients with acute monosymptomatic unilateral ON of whom 33 had progressed to MS after up to 18 years. Three patients had died. The present study extends the observation period to 31 years. METHODS: Patients were followed for up to 31 years or until a diagnosis of MS was made. Cerebrospinal fluid (CSF) was examined at onset. HLA class I and II antigens were determined. Magnetic Resonance Imaging (MRI) was performed during follow up. FINDINGS: Only one of 50 patients at risk developed clinical manifestations of MS during the extended follow up period. The estimated 15-year-risk of MS was 40 % (confidence interval [CI] 31%-52%). Most cases, 20 of 34 or 60%, occurred within three years. Among factors present at onset, CSF with mononuclear pleocytosis and/or oligoclonal Ig increased the risk for subsequent MS significantly, 49% (CI 38%-65%) compared with 23 % (CI 12%-44%) for those with normal CSF, p=0.02. Younger patients and those with winter onset also had greater risk. Recurrence of ON similarly elevated the risk significantly, p<0.001. After 19-31 years MRI lesions suggestive of demyelinating disease were detected in 20 of 30 individuals although no clinical manifestations of MS had occurred. CONCLUSION: The risk of MS in this large population-based prospective ON patient series was 40% and significantly higher in those with inflammatory CSF abnormalities at onset. Clinically silent MRI lesions suggestive of MS were detected in a majority of those with "ON-only". This finding should be taken into account when discussing prognosis and early intervention in patients with clinically isolated ON.

Two genome-wide linkage disequilibrium screens in Scandinavian multiple sclerosis patients.

We report the first two genome-wide screens for linkage disequilibrium between putative multiple sclerosis (MS) susceptibility genes and genetic markers performed in the genetically homogenous Scandinavian population, using 6000 microsatellite markers and DNA pools of approximately 200 MS cases and 200 controls in each screen. Usable data were achieved from the same 3331 markers in both screens. Nine markers from eight genomic regions (1p33, 3q13, 6p21, 6q14, 7p22, 9p21, 9q21 and Xq22) were identified as potentially associated with MS in both screens.