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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.

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.

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 2011

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 diseaseand 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.

The clinical applicability of the revised McDonald diagnostic criteria of primary progressive multiple sclerosis (PPMS) was assessed in 17 patients with a longstanding PPMS diagnosis (mean 15 years). All patients were re-evaluated with clinical examinations, magnetic resonance imaging (MRI) of the brain and the spinal cord, extensive laboratory tests, and 12 patients underwent cerebrospinal fluid (CSF) examination. No diagnosis more likely than PPMS was disclosed. All patients had brain and spinal cord lesions on MRI. In 15 patients the brain lesions and in 14 the spinal cord lesions fulfilled the revised McDonald criteria for positive scans. No contrast-enhancing lesion was observed despite administration of triple doses of gadolinium. In total, 12 patients fulfilled the revised McDonald MRI criteria for PPMS. Of the remaining five patients who incompletely fulfilled the revised MRI criteria, all had CSF findings supporting the diagnosis PPMS. Thus, CSF analysis was required in addition to MRI in about one-third of the patients to establish the diagnosis of PPMS. Udgivelsesdato: 2007-Nov

In this study, the results from three Nordic linkage disequilibrium screens in multiple sclerosis (MS) were investigated, in a new sample set of 314 Nordic MS trios from Denmark, Norway, Sweden and Iceland. Among 30 non-HLA and two HLA microsatellite markers individually genotyped, eight markers displayed distorted transmission with uncorrected P-value

Background: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment. Methods: We examined individual patient data from eight clinical trials with IFNβ-1a. Results: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNβ-1a (in utero exposure group), 22 were patients who discontinued IFNβ-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy) Conclusions: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNβ therapy before becoming pregnant.

Objective: To determine the incidence and clinical significance of neutralizing antibody (NAb) formation in patients with relapsing multiple sclerosis ( MS) who participated in the European Interferon Beta-1a IM Dose-Comparison Study. Methods. Patients were randomized to treatment with interferon beta-1a (IFN beta-1a) 30 mu g or 60 mu g IM once weekly for up to 4 years. Serum samples obtained at baseline and every 3 months thereafter were screened for the presence of IFN binding antibodies by ELISA. Patients whose results were seropositive on ELISA were screened for the presence of NAbs using an antiviral cytopathic effect assay. Patients were considered to be positive for NAbs ( NAb+) if the baseline NAb titer was 0 and two or more consecutive postbaseline titers were >= 20. Patients were considered to be negative for NAbs ( NAb -) if the baseline NAb titer was 0 and all postbaseline NAb titers were < 5. Results: The proportion of patients who became NAb + was lower in patients who received 30 mu g of IFN beta-1a than in those who received 60 mu g (7/400 [1.8%] vs 19/395 [4.8%]; p = 0.02). The mean time to NAb + status was 14.5 +/- 6.2 months. Compared with patients who remained NAb -, NAb + patients showed the following: higher relapse rates from months 12 to 48 ( p = 0.04), higher rate of mean change ( worsening) in Expanded Disability Status Scale score from baseline to month 48 ( p = 0.01), greater number of T1 gadolinium-enhanced lesions at months 24 and 36 ( p = 0.02 and 0.03), and greater accrual of new or enlarging T2 lesions from month 12 to months 24 and 36 ( p = 0.05 and 0.09) Conclusions: Neutralizing antibodies ( NAbs) to interferon beta-1a (IFN beta-1a), as observed with other IFN beta s used in the treatment of multiple sclerosis, reduce the therapeutic benefits measured by relapses and MRI activity. Data from this study also suggest NAbs to IFN beta-1a reduce treatment benefits as measured by change in Expanded Disability Status Scale score. (Less)

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. (Less)

Background: Laquinimod is a novel immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability, and efficacy on MRI lesions of two different doses of laquinimod compared with placebo in patients with relapsing MS. Methods: In this multicenter, double-blind, randomized trial, patients with relapsing MS received 0.1 mg or 0.3 mg laquinimod or placebo as three daily tablets for 24 weeks. Gadolinium-enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment. The primary efficacy variable was the cumulative number of active lesions over 24 weeks. Safety measures included adverse events, physical examination, and laboratory variables. Results: Of 256 screened patients, 209 were randomized (67 to 74 patients per group) in 20 centers. There was a significant difference between laquinimod 0.3 mg and placebo for the primary outcome measure (mean cumulative number of active lesions reduced by 44%). In the subgroup of patients with at least one active lesion at baseline the reduction was slightly more pronounced (52%). No differences with respect to clinical variables (relapses, disability) were found. The safety profile was favorable; there were no clinical signs of undesired inflammatory manifestations. Conclusion: Oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis.

The EVIDENCE study was a direct comparative study of two dose regimens of interferon (IFN) beta-1a used in the treatment of relapsing-remitting multiple sclerosis (RRMS): 30 mcg intramuscularly once weekly (qw; n=338) and 44 mcg subcutaneously three times weekly (tiw; n=339). The study continued for an average of 64 weeks. The safety population consisted of all patients receiving at least one dose of study drug. Clinical assessments occurred every 4 weeks for 24 weeks and then every 12 weeks. Blood tests for safety were taken at baseline and at weeks 4 and 12, and every 12 weeks thereafter. Overall adverse events were more common with the 44 mcg tiw regimen (p=0.007), and were due predominantly to differences in injection-site reactions. The majority of adverse events were rated mild by investigators. Hepatic and haematological adverse events and asymptomatic laboratory abnormalities were more common with 44 mcg tiw (p

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.

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.

Genetic factors influence susceptibility to multiple sclerosis but the responsible genes remain largely undefined, association with MHC class II alleles being the only established genetic feature of the disease. The Nordic countries have a high prevalence of multiple sclerosis, and to further explore the genetic background of the disease, we have carried out a genome-wide screen for linkage in 136 sibling-pairs with multiple sclerosis from Denmark, Finland, Norway and Sweden by typing 399 microsatellite markers. Seventeen regions where the lod score exceeds the nominal 5% significance threshold (0.7) were identified-1q11-24, 2q24-32, 3p26.3, 3q21.1, 4q12, 6p25.3, 6p21-22, 6q21, 9q34.3, 10p15, 10p12-13, 11p15.5, 12q21.3, 16p13.3, 17q25.3, 22q12-13 and Xp22.3. Although none of these regions reaches the level of genome-wide significance, the number observed exceeds the 10 that would be expected by chance alone. Our results significantly add to the growing body of linkage data relating to multiple sclerosis.

Objective: To provide recommendations on the use of disease-modifying agents in the management of multiple sclerosis (MS) and to ensure that treatment will be available to those patients who may benefit. Methods: An initial draft of the consensus statement was prepared by the Steering Committee and amended in the light of written comments from a group of MS specialists. At a subsequent workshop, the wording of the consensus statement was discussed, modified if necessary, and the participants indicated their level of support using an electronic voting system. A new draft of the statement was then sent to a much larger group of international opinion leaders in MS for further comment. Results: A number of statements were agreed, which outline the criteria for consideration of disease-modifying therapy for MS and recommendations for treatment. Each statement was accepted completely, or with only minor reservations by 95% or more of those present at the workshop. Conclusions: Periodic reviews and modifications to the statement will be required, as new approaches to the treatment of MS and other therapeutic agents become available.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) of unknown etiology. Nitric oxide (NO) is a free radical that participates in a variety of biological processes. It is an important mediator in the immune response. Several studies indicate involvement of NO in the pathogenesis of MS. We studied five markers within the three NO synthase genes with regards to susceptibility and disease course in 156 affected sib-pairs and in 96 “benign” and 96 “severe” definite MS patients and 148 controls. We found no significant association or evidence for linkage in our data sets.

The T cell specific adapter protein (TSAd) encoded by the SH2D2A gene is involved in the control of T cell activation. The gene is located in the 1q21 region, which has been implicated in susceptibility to experimental allergic encephalomyelitis in the mouse. We therefore evaluated whether a polymorphic GA repeat (GA(13)-GA(33)) within the promoter region of the SH2D2A gene shows association to multiple sclerosis (MS). The frequency of the short alleles GA(13-16) was increased among 313 Norwegian MS patients compared to 277 healthy controls (0.332 vs 0.249, OR 1.5, Pc = 0.03). Transmission disequilibrium analysis in 146 Scandinavian families with at least two affected sibs showed increased transmission of GA(16) to MS patients. No linkage or association of MS to four genetic markers flanking the SH2D2A gene was observed. After activation of naive CD4(+) T cells, T cells homozygous for MS associated short alleles displayed lower level of TSAd ex vivo than T cells carrying at least one long allele, which were not associated to MS. Since the SH2D2A protein modulates T cell activation, this may be a mechanism for how short SH2D2A alleles confer susceptibility to develop MS.

The proinflammatory cytokine interferon (IFN)-gamma has been shown to influence the course of multiple sclerosis (MS). The IFN-gamma (IFNG) contains a multiallelic dinucleotide repeat in intron 1. To investigate whether alleles at this locus influence susceptibility to MS, we performed linkage and familial association analyses on 100 sibling pairs from four Nordic countries, and case-control association analysis on 220 intermediately disabled sporadic MS patients and 266 controls. To determine the effect of the polymorphism on disease outcome, we compared genotype frequencies in the most and least disabled octiles of a total cohort of 913 cases. We also measured IFN-gamma mRNA levels in unstimulated peripheral blood mononuclear cells from 46 MS patients and 27 controls grouped according to IFNG intron 1 genotype. Both nonparametric linkage analysis and transmission disequilibrium testing of the 100 sibling pairs produced negative results. Genotype frequencies for intermediate-MS patients did not differ significantly from those for controls; nor did genotype frequencies in the benign-MS octile differ significantly from those in the severe-MS octle. Comparison of IFN-gamma mRNA levels in genotype-conditioned subgroups revealed no significant differences. Thus, alleles at the IFNG intron 1 dinucleotide repeat appear to affect neither MS susceptibility and severity nor IFN-gamma mRNA expression in vivo.

The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

To date, four genome screens have been completed in the demyelinating autoimmune disease multiple sclerosis (MS). Although these screens failed to identify any loci with major effects on susceptibility, several novel regions of potential linkage were suggested, including the long arm of chromosome 17. In order to further pursue this promising region we have investigated six highly polymorphic microsatellite markers in 115 Scandinavian families with MS affected sib pairs. Multipoint linkage analysis revealed a peak maximum likelihood score (MLS) of 0.9 in the region of marker D17S787. Stratifying the results on the basis of HLA-DR2 status showed that the linkage was not limited to families segregating for the HLA-DR2 allele as has previously been suggested. In conclusion, our results further support the proposal that a multiple sclerosis susceptibility locus is contained on chromosome 17q.

In the genetically homogeneous Scandinavian population, we have investigated chromosome 5 and the HLA (human leukocyte antigen) region on chromosome 6p21 by applying linkage and association analyses on 106 white sibling pair families with multiple sclerosis. The importance of genes within the HLA region for the susceptibility of multiple sclerosis has previously been reported. More recently, findings have suggested importance of regions on chromosome 5. Half of chromosome 5 was analyzed by using 14 microsatellite markers and a susceptibility region with a maximum LOD score of 1.1 was identified. Chromosome 6 was analyzed by HLA-DR typing and using the TNF alpha microsatellite marker. A peak maximum LOD score of 2.0 was found at the HLA-DR marker. Association studies were made for all the markers, comparing 106 probands from the sibling pairs with 100 unrelated controls. None of the markers on chromosome 5 showed significant association with multiple sclerosis, whereas strong association between multiple sclerosis and DR2 was found, with an odds ratio of 3.7 (p < 10(-5)). It is surprising that association was not seen for any of the TNF alpha alleles including the 121-bp allele, although this allele was in positive linkage disequilibrium with DR2 in both patients and controls. Our results support the existence of multiple sclerosis susceptibility loci on chromosomes 5p and 6p21.

Multiple sclerosis (MS) is an oligo- or polygenic disease but no specific susceptibility genes have been identified so far. In the Finnish population we have previously found evidence for linkage between MS and the myelin basic protein gene (here called Golli-MBP gene) suggesting that either Golli-MBP or another gene in its vicinity contributes to MS suceptibility. Here we have screened the Golli-MBP gene for nucleotide variations and carried out multipoint association analyses in a Finnish case-control data-set as well as in an independent data-set composed of 151 MS families from Finland and Sweden. In both data-sets we found association between MS and alleles in the 1.27 kilobase (kb) range at a tetranucleotide repeat element (TGGA)n which is located 1 kb upstream of the MBP exon 1. Haplotype analyses suggested that the MS-associated 1.27 kb alleles can be split into predisposing and non-predisposing variants and provided evidence that the candidate DNA region contributing to MS susceptibility should be located at the Golli-MBP gene within a 20-25 kb segment that was conserved in the predisposing haplotypes. These findings suggest a role for the Golli-MBP locus in MS susceptibility, at least in a subset of patients, and serve as a basis for highly focused attempts to identify predisposing mutation(s).

A non-radioactive technique for the typing of tumour necrosis factor (TNF) microsatellite alleles has been applied in the study of an Italian population. The frequency of the TNFa 10 allele was markedly increased compared with other European populations.

We have analyzed the distribution of tumor necrosis factor (TNF) a and-b microsatellite alleles in HLA-DQ and-DR typed Swedish patients with multiple sclerosis (MS) (n=l22) and ethnically matched control subjects (n=l78). We found significant differences in the frequencies of TNFa and TNFb alleles between patients and controls. TNFal I was significantly associated with MS. This was also the case for the combination of TNFal I with TNFb4. However, TNFal I (alone or in combination with TNFb4) did not show any disease association independent of DQA 1*01021 DQBI*0602/DR2, whereas the previously reported strong association with HLA-DQAI*0102/DQBI*0602/DR2 in Scandinavian populations was confirmed. Therefore the association of TNFal I (and TNFb4) is most likely secondary to the increase of DQAI*0102/DQBl*0602/DR2 in MS patients. The proportion of TNFa6 positive individuals was lower among DR2-negative MS patients than among DR2-negative controls (p=0.08). Since the presence of the TNFab allele correlates with low TNFα production in response to lipopolysaccharide, it could be speculated that DR2-negative MS patients have an increased risk of being high TNFα producers in response to exogenous stimuli.

The association of MS with HLA class II alleles was studied by PCR-based typing of the DQA1, DQB1, DRB1, and DPB1 loci in 94 Swedish patients with relapses and remissions of the disease. The haplotype DRB1*1501-DQA1*0102-DQB1*0602 was found to be positively associated and three haplotypes were found to be negatively associated with MS. Linkage disequilibrium makes it difficult to assess whether DRB1 or DQB1 plays the primary role in the disease association, while the association with DPB1 and DQA1 appears to be secondary to that of DQB1 and DRB1. Two of the three haplotypes negatively associated with MS carry the DQB1*0301 allele. Also, the negatively associated DRB1*0401-DQA1*0301-DQB1*0301 haplotype differs from those with nonassociated DRB1*0401-DQA1*0301-DQB1*0302 haplotype only at DQB1. These results suggest that DQB1 alleles, as well as some DRB1 alleles, are involved in susceptibility and protection to MS. In searching for sequence motifs in the DR beta chain associated with MS susceptibility, all DRB1 alleles on haplotypes positively associated with MS, including the DRB1*1501, were found to encode a Val at position 86 of the DR beta chain. Also, DRB1 alleles that are negatively associated with MS all encode a Gly at position 86, suggesting that the residue at position 86 may be critical in conferring susceptibility and protection to MS. Finally, when the effect of the DRB1*1501 haplotype was removed there was no support for the hypothesis that MS is associated with a putative DQ-alpha beta heterodimer, encoded for by certain DQA1 and DQB1 alleles.

Risks that are potentially associated with long-term therapies should be assessed.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.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.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.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.

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.

An immunocytochemical study of surface and cytoplasmic markers of the monocyte/macrophage lineage was undertaken on peripheral blood (PB) and cerebrospinal fluid (CSF) cells in patients with multiple sclerosis (MS) or other neurological diseases (OND) and in three healthy controls. Size and granularity were assessed by means of cytofluorimetric analysis. Fewer monocytes were positive for complement receptors 1 and 3, myeloperoxidase, KiM6, IOM-3 and CD14 in CSF than in PB. Only DR-positive monocytes were present with the same frequency in the two compartments. There was no difference in the monocyte phenotype between patients and healthy controls. Furthermore, there was no difference between patients with MS or OND. Cytofluorimetric analysis showed that in CSF, regardless of clinical status, few cells displayed the physical features of blood monocytes. A population of granular and large granular cells that was not normally present among PB mononuclear cells was recognized in the CSF. A large proportion of these cells was able to adhere to plastic and - when sorted - displayed the morphology and surface markers of monocyte lineage. The results of our study demonstrate compartment-specific differences in the monocyte phenotype between CSF and PB but suggest that these changes may be unrelated to the investigated neurological diseases.

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

The authors undertook a controlled, prospective, randomized study of 171 patients with supratentorial astrocytoma grades 3 and/or 4 (classified according to Kernohan). All patients were given chemotherapy consisting of procarbazine, vincristine, and lomustine (CCNU) (PVC). Half of the patients received whole-brain irradiation (RT) to a dose of 5800 cGy in the tumor-bearing hemisphere and 5000 cGy in the contralateral hemisphere. After diagnosis of progressive tumor growth, patients received individual treatment. The endpoint of the study was time to progression, but cases were followed until the patients died. Median time to progression (MTP) for the whole randomized population was 21 weeks. Median survival time (MST) was 53 weeks; 18% of patients survived for 2 years or longer. Survival analysis showed that patients less than 50 years of age treated with PVC plus RT had significantly longer MTP (81 weeks) and MST (124 weeks) than all other patients. For patients less than 50 years of age treated with PVC alone, MTP was 21 weeks and MST was 66 weeks. For patients more than 50 years of age treated with PVC plus RT, MTP was 23 weeks and MST was 51 weeks; in the PVC group, MTP was 17 weeks and MST was 39 weeks. Age, Karnofsky index, areas of Grade 2, and absence of extensive necrosis in the tumor were significant prognostic factors in the univariate analyses. Patients less than 50 years of age treated with PVC plus RT had significantly longer survival (P = 0.037) when correcting for these factors in a multi-variate analysis.

A method employing long-term lymphocyte culturing was developed to study chromosome aberrations in samples with very few cells. It was used to examine lymphocytes from the cerebrospinal fluid (CSF) and peripheral blood (PB) in 23 patients with clinically definite multiple sclerosis (MS), nine patients with other neurological diseases (OND), and eight healthy individuals. MS patients had significantly more aberrations in CSF lymphocytes than in PB lymphocytes (6.4 vs 4.1; P = 0.003). In contrast, no such difference was noted among patients with OND (3.8 vs. 3.7; P = 0.89) or healthy controls (3.6 vs 3.5; P = 0.90). CSF lymphocytes from MS patients had more aberrations than CSF lymphocytes from healthy controls (P = 0.012), but there was no difference between PB lymphocytes from MS patients and controls (P = 0.58). The patients with OND were similar to healthy controls both in CSF (3.8 vs 3.6; P = 0.91) and PB lymphocytes (3.7 vs 3.5; P = 0.90).

Objective Cognitive dysfunction is common in multiple sclerosis (MS), but long-term data on cognition in patients with clinically isolated syndromes are sparse. Methods We determined cognitive functions in 22 patients 44–75 years old diagnosed with optic neuritis 24–31 years earlier but had no further clinical bouts and had not progressed clinically to MS. We used a neuropsychological test battery covering nine cognitive domains. Magnetic resonance imaging (MRI) of the brain had been performed earlier and was normal in six patients and showed two or more white matter abnormalities compatible with demyelinating lesions in 16 patients. Results On neuropsychological testing, one patient was within normal range on all tests, six subjects showed borderline results, and 15 patients (68%) showed significantly impaired performance in at least one cognitive domain. Seven patients showed significant impairment in two or more domains. Executive function, visuo-spatial ability, and information processing speed were the most frequently affected domains. There was no apparent correlation between MRI findings and cognitive function. Conclusions We conclude that cognitive dysfunction is common in patients many years after clinically isolated optic neuritis. Cognitive dysfunction was found even in patients who had no apparent demyelinating lesions on follow-up MRI.

Eighty-six patients with monosymptomatic optic neuritis of unknown cause were followed prospectively for a median period of 12.9 years. At onset, cerebrospinal fluid (CSF) pleocytosis was present in 46 patients (53%) but oligoclonal immunoglobulin in only 40 (47%) of the patients. The human leukocyte antigen (HLA)-DR2 was present in 45 (52%). Clinically definite multiple sclerosis (MS) was established in 33 patients. Actuarial analysis showed that the cumulative probability of developing MS within 15 years was 45%. Three risk factors were identified: low age and abnormal CSF at onset, and early recurrence of optic neuritis. Female gender, onset in the winter season, and the presence of HLA-DR2 antigen increased the risk for MS, but not significantly. Magnetic resonance imaging detected bilateral discrete white matter lesions, similar to those in MS, in 11 of 25 patients, 7 to 18 years after the isolated attack of optic neuritis. Nine were among the 13 with abnormal CSF and only 2 belonged to the group of 12 with normal CSF (p = 0.01). Normal CSF at the onset of optic neuritis conferred better prognosis but did not preclude the development of MS.

The Nco I tumor necrosis factor (TNFα) polymorphism was studied in relapwing/remitting multiple sclerosis and monosymptomatic optic neuritis. The frequency of the Nco I marker phenotypes did not differ between healthy controls and the two disease groups. No extra or missing DNA fragments were observed in the disease groups when compared with controls.

Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-β1a (IFN-β1a), 22 μg subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-β1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS

Contains fulltext : 50685.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. RESULTS: LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. CONCLUSIONS: Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.

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.

In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib-pair families, 222 British sib-pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA-DR DQ haplotype, and the Norwegian case-control samples were also typed for HLA-A and -B loci. In the Norwegian sporadic MS patients association was seen with HLA-A, HLA-B, and with the D6S265 marker, located 100 kb centromeric to HLA-A. Associations with HLA-A and D6S265 loci were also suggested when restricting the analysis to HLA-DR15 haplotypes. In the sib-pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA-DR15 and -A3 (GRR = 15), compared to those who carry only HLA-DR15 (GRR = 7), only HLA-A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA-DR15 and -A3 (odds ratio (OR) = 5.2). These results suggest that HLA-A or a gene in linkage disequilibrium with it may contribute to the HLA class II-associated genetic susceptibility to MS.

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.

Four genomic screens for linkage in multiple sclerosis (MS) have been reported. They confirmed the established role of the human leucocyte antigen (HLA) complex genes in MS and, in addition, suggested the importance of a few other chromosomal segments. Here we report evidence for the importance of 3p14-13 region identified by suggestive linkage in genomic screens from Canada and the United Kingdom. When studying 146 Nordic MS multiplex families, mostly affected sib-pairs, with eight microsatellite markers, spanning a 36-cM region, we observed a two-point non-parametric linkage (NPL) score of 2.39 (P = 0.007) by the GENEHUNTER package for marker D3S1285 and a multipoint NPL score of 1.20 in the same region. Association studies in Swedish MS patients revealed modest allelic associations of uncertain significance not supported by transmission analysis. Analysis of the trinucleotide repeat sequence of the SCA7 gene in Swedish index cases did not reveal expansions. We conclude that support was obtained for the location of a gene or genes with importance for MS susceptibility in 3p14-13 region.

Multiple sclerosis (MS) is probably caused by an interaction of genetic and environmental factors. The genetic component is reflected by a ten-fold higher concordance rate in monozygotic (27%) compared to dizygotic (3%) twin pairs. Treatment with interferon was recently reported to have a favorable effect in patients with relapsing-remitting MS. In the present familial study, we have investigated the possibility of a genetic association between the highly polymorphic Interferon alpha beta locus and the development of MS. Based on our data, we conclude that there is no linkage between the Interferon alpha beta locus and MS.

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Several observations suggest that the interferon system may be of interest in the study of MS development. To investigate whether polymorphism in components of the IFN system and the JA K-STAT pathway influence susceptibility to MS, we performed a linkage analysis between polymorphic loci in or close to the IFN gamma, IFN gamma recepto r, IFN alpha/beta recepto r, JA K 1, STAT 1 and STAT 3 genes in 27 Swedish families with at least two members having MS. Tests for transmission disequilibrium and nonparametric linkage analysis gave negative results. We found no evidence for linkage between MS and any of these loci.

We studied the allelic constitution at the HLA class II DQA1, DQB1, DRB1 and DPB1 in 94 Italian multiple sclerosis (MS) patients and 98 controls. No significant increase in the frequency of DR2 alleles was detected among MS patients, as previously observed both in European and some Italian studies. A slight increase was found for the DQA1*0301 and DQB1*0602 alleles in the MS patients. No significant association was found with the glutamine residue at position 34 of the DQ alpha chain, which was noted previously in MS patients from northern Europe.

The relationship between multiple sclerosis (MS) and primary Sjogren's syndrome (PSS) is ambiguous; it was suggested that some patients diagnosed with MS may instead have PSS. In a recent epidemiologic study, the prevalence of PSS was 2.7% in southern Sweden. We randomly selected 30 patients with definite MS from our patient population and investigated them for evidence of PSS according to the Copenhagen criteria. One patient had clinical symptoms compatible with PSS and also fulfilled the Copenhagen criteria. In addition, five patients had keratoconjunctivitis sicca, one had xerostomia, and three had histopathologic evidence of sialadenitis in the lower lip salivary glands. However, one of these findings alone is not sufficient to support the diagnosis of PSS. We conclude that MS and PSS may coexist in the same individual, but PSS is not more common among MS patients than expected in the general population.

We have studied the germline repertoire of T-cell receptor β chain genes in 20 patients with monosymptomatic optic neuritis (ON), which may mark the onset of MS, and in 37 patients with relapsing/remitting (R/R) MS; we compared this repertoire to that of 99 unselected, unrelated healthy Danes

DP gene typing using in vitro DNA amplification combined with sequence-specific oligonucleotide probes (SSOP) has recently been reported. The amplification step may be specific for the HLA-DPB locus, or it may be specific for one or a group of HLA-DPB alleles, thus increasing the discriminatory power of the system. We report the combined use of group-specific DNA in vitro amplification followed by SSOP in typing for DPB1*02 and DPB1*04 variants. The method was used to type for these variants in 96 randomly selected, healthy Danes, in 37 patients with pauciarticular juvenile rheumatoid arthritis (PJRA), and in 38 patients with multiple sclerosis (MS). Increased frequencies of the cellularly defined HLA-DPw2 in PJRA and of HLA-DPw4 in MS have previously been reported. In the patient groups, the frequencies of the DPB1*02 and DPB1*04 variants did not differ significantly from those expected based on the cellularly defined HLA-DP types of the patients and the frequencies of the DPB1*02 and DPB1*04 variants among healthy Danes.