Bernard M. J. Uitdehaag

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10−11), IRF8 (P = 3.73 × 10−9) and CD6 (P = 3.79 × 10−9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease (REGARD) study): a multicentre, randomised, parallel, open-label trial

BACKGROUND Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS. METHODS In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 mug subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338. FINDINGS Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0.94, 95% CI 0.74 to 1.21; p=0.64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0.24 vs 0.41 lesions per patient per scan, 95% CI -0.4 to 0.1; p=0.0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks. INTERPRETATION There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS.

Pathway and network-based analysis of genome-wide association studies in multiple sclerosis

Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.

Safety, tolerability, and efficacy of orally administered cannabinoids in MS

Abstract—The authors conducted a randomized, double-blind, placebo-controlled, twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety, tolerability, and efficacy of oral &Dgr;9-Tetrahydrocannabinol (THC) and Cannabis sativa plant extract. Both drugs were safe, but adverse events were more common with plant-extract treatment. Compared with placebo, neither THC nor plant-extract treatment reduced spasticity. Both THC and plant-extract treatment worsened the participant’s global impression.

Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI

Background: Different double inversion recovery (DIR) sequences are currently used in multiple sclerosis (MS) research centers to visualize cortical lesions, making it difficult to compare published data. This study aimed to formulate consensus recommendations for scoring cortical lesions in patients with MS, using DIR images acquired in 6 European centers according to local protocols. Methods: Consensus recommendations were formulated and tested in a multinational meeting. Results: Cortical lesions were defined as focal abnormalities on DIR, hyperintense compared to adjacent normal-appearing gray matter, and were not scored unless ≥3 pixels in size, based on at least 1.0 mm2 in-plane resolution. Besides these 2 obligatory criteria, additional, supportive recommendations concerned a priori artifact definition on DIR, use of additional MRI contrasts to verify suspected lesions, and a constant level of displayed image contrast. Robustness of the recommendations was tested in a small dataset of available, heterogeneous DIR images, provided by the different participating centers. An overall moderate agreement was reached when using the proposed recommendations: more than half of the readers agreed on slightly more than half (54%) of the cortical lesions scored, whereas complete agreement was reached in 19.4% of the lesions (usually larger, mixed white matter/gray matter lesions). Conclusions: Although not designed as a formal interobserver study, the current study suggests that comparing available literature data on cortical lesions may be problematic, and increased consistency in acquisition protocols may improve scoring agreement. Sensitivity and specificity of the proposed recommendations should now be studied in a more formal, prospective, multicenter setting using similar DIR protocols.

Suppression of experimental allergic encephalomyelitis by intraventricular administration of interferon-gamma in Lewis rats

Experimental allergic encephalomyelitis (EAE) is an autoimmune inflammatory disease of the central nervous system (CNS) which causes paralysis. Several studies have reported the involvement of Ia antigen‐expressing cells in the pathogenesis of EAE. Interferon‐gamma (IFN‐γ) can induce Ia antigen expression on a wide range of cells. We examined the effect of IFN‐γ on EAE in Lewis rats. Systemically administered IFN‐γ did not change the disease course of EAE, whereas IFN‐γ applied locally into the ventricular system of the CNS resulted in complete suppression of clinical signs. Furthermore, we found that systemic administration of anti‐IFN‐γ just prior to the onset of clinical symptoms resulted in a more severe disease course. We conclude that IFN‐γ is capable of exerting a suppressive action in EAE, possibly through induction of Ia antigen expression or through the induction of suppressive mechanisms locally in the CNS.

Diagnostic value of high-resolution sonography in ulnar neuropathy at the elbow

Objective: To determine the diagnostic value of high-resolution sonography in ulnar neuropathy at the elbow (UNE). Methods: Sonographic ulnar nerve diameter measurement was compared at three levels around the medial epicondyle with a criterion standard including clinical and electrophysiologic characteristics in a cohort of 123 patients presenting with clinical signs of UNE. UNE or probable UNE was diagnosed in 84 patients and a different condition in 39 patient controls. Reference values were obtained in 56 healthy volunteers. Results: One hundred thirty-six affected arms were studied in 123 patients (UNE in 82, probable UNE in 9, and a different condition in 45 affected arms). Patients with UNE had a larger ulnar nerve diameter than patient controls (p < 0.0001). The sensitivity of sonography was 80%, specificity 91%, positive likelihood ratio 9, and negative likelihood ratio 0.2. The highest diagnostic yield was found in patients in whom electrodiagnostic studies showed signs of ulnar neuropathy but could not localize the lesion (17/20 cases, 86%) and in patients who had motor conduction velocity slowing across the elbow without conduction block (32/37 cases, 86%). Conclusions: High-resolution sonography is an accurate and easily applied test for the diagnosis of UNE. The authors recommend its use in addition to electrodiagnostic studies because it improves the reliability of the diagnosis of UNE.

A systematic review of Instrumental Activities of Daily Living scales in dementia: room for improvement

Background: Instrumental Activities of Daily Living (IADL) questionnaires can be helpful in diagnosing dementia and are often used for clinical follow-up and treatment evaluation in dementia patients. Despite the large number of questionnaires, their quality has received little attention. Objective: To systematically review the measurement properties of all available structured informant-based (I)ADL questionnaires, developed or validated for use in demented patients. Methods: A systematic literature search was conducted in MEDLINE, PsycINFO and EMBASE for psychometric articles on (I)ADL questionnaires. In addition, reference lists of all retrieved articles were screened. Standardised criteria were used to assess the quality of the measurement properties. When possible, investigators were contacted to obtain missing information. Two authors independently extracted studies and performed the quality assessment of the questionnaires. Findings: Thirty-two articles were selected, covering 12 (I)ADL questionnaires. Information on 52.3% of the quality aspects was not available, 32.4% of the ratings were indeterminate, 8.1% were positive, and 7.2% were negative. Out of eight measurement properties, two scales (the DAD and the Bristol ADL) received two positive ratings and were classified as of moderate quality. Five scales (ADL-PI, ADL-IS, B-ADL, CSADL and Lawton IADL) received one positive rating. Interpretation: The findings indicate that improvements in and more data on psychometric properties of (I)ADL questionnaires for dementia patients are necessary in order to justify their use.

Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial

BACKGROUND In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event. METHODS We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18-50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352. FINDINGS 517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p<0·0001, hazard ratio [HR] 0·49 [95% CI 0·38-0·64]; once a week 75·5%, p=0·008, HR 0·69 [0·54-0·87]) versus placebo (85·8%). 2-year rates of conversion to CDMS were lower for both interferon beta-1a dosing regimens (three times a week 20·6%, p=0·0004, HR 0·48 [0·31-0·73]; once a week 21·6%, p=0·0023, HR 0·53 [0·35-0·79]) than for placebo (37·5%). Adverse events were within the established profile for subcutaneous interferon beta-1a. INTERPRETATION Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study. FUNDING Merck Serono SA, Geneva, Switzerland.

Brain atrophy and lesion load predict long term disability in multiple sclerosis

Objective To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS). Design From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1–2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing–remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0–3.5, n=111) or moderately impaired (EDSS=4–6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores. Results In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R2=0.74 in the whole group and R2=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R2=0.68), lesion volumes in moderately impaired relapse onset patients (R2=0.21) and whole brain atrophy in primary progressive MS (R2=0.34). Conclusions This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.