Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis--establishing disease prognosis and monitoring patients.

The role of MRI in the assessment of multiple sclerosis (MS) goes far beyond the diagnostic process. MRI techniques can be used as regular monitoring to help stage patients with MS and measure disease progression. MRI can also be used to measure lesion burden, thus providing useful information for the prediction of long-term disability. With the introduction of a new generation of immunomodulatory and/or immunosuppressive drugs for the treatment of MS, MRI also makes an important contribution to the monitoring of treatment, and can be used to determine baseline tissue damage and detect subsequent repair. This use of MRI can help predict treatment response and assess the efficacy and safety of new therapies. In the second part of the MAGNIMS (Magnetic Resonance Imaging in MS) network's guidelines on the use of MRI in MS, we focus on the implementation of this technique in prognostic and monitoring tasks. We present recommendations on how and when to use MRI for disease monitoring, and discuss some promising MRI approaches that may be introduced into clinical practice in the near future.

Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis-clinical implementation in the diagnostic process.

The clinical use of MRI in patients with multiple sclerosis (MS) has advanced markedly over the past few years. Technical improvements and continuously emerging data from clinical trials and observational studies have contributed to the enhanced performance of this tool for achieving a prompt diagnosis in patients with MS. The aim of this article is to provide guidelines for the implementation of MRI of the brain and spinal cord in the diagnosis of patients who are suspected of having MS. These guidelines are based on an extensive review of the recent literature, as well as on the personal experience of the members of the MAGNIMS (Magnetic Resonance Imaging in MS) network. We address the indications, timing, coverage, reporting and interpretation of MRI studies in patients with suspected MS. Our recommendations are intended to help radiologists and neurologists standardize and optimize the use of MRI in clinical practice for the diagnosis of MS.

Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial.

OBJECTIVE: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population. RESULTS: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported. CONCLUSION: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Longitudinal JCV serology in multiple sclerosis patients preceding natalizumab-associated progressive multifocal leukoencephalopathy.

The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MS patients treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. We here describe extensive longitudinal serum anti-JCV antibody indexes of four MS patients who developed PML. Anti-JCV antibodies were measured using the STRATIFY JCV™DxSelect™ test. All four patients had rather stable high anti-JCV antibody indexes in all samples obtained before developing PML. Possibly caused by reaching the saturation level of the assay, no increase in anti-JCV antibody indexes was seen just before the diagnosis of PML. This study confirms that high serum anti-JCV antibody indexes precede natalizumab-associated PML.

Functional brain networks: linking thalamic atrophy to clinical disability in multiple sclerosis, a multimodal fMRI and MEG study.

Thalamic atrophy is known to be one of the most important predictors for clinical dysfunction in multiple sclerosis (MS). As the thalamus is highly connected to many cortical areas, this suggests that thalamic atrophy is associated with disruption of cortical functional networks. We investigated this thalamo-cortical system to explain the presence of physical and cognitive problems in MS. Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) were performed in 86 MS patients and 21 healthy subjects. We computed cortical functional networks for fMRI and MEG by respectively the Pearson's correlation coefficient and the phase lag index using the same automated anatomical labeling atlas for both modalities. Thalamo-cortical functional connectivity was only estimated using fMRI. We computed conventional network metrics such as clustering coefficient and path length and analyzed the minimum spanning tree (MST), a subnetwork and backbone of the original network. MS patients showed reduced thalamic volumes and increased thalamo-cortical connectivity. MEG cortical functional networks showed a lower level of integration in MS in terms of the MST, whereas fMRI cortical networks did not differ between groups. Lower integration of MEG cortical functional networks was both related to thalamic atrophy as well as to increased thalamo-cortical functional connectivity in fMRI and to worse cognitive and clinical status. This study demonstrated for the first time that thalamic atrophy is associated with global disruption of cortical functional networks in MS and this global disruption of network activity was related to worse cognitive and clinical function in MS. Hum Brain Mapp 36:603-618, 2015. © 2014 Wiley Periodicals, Inc.

Toward the use of proxy reports for estimating long-term patient-reported outcomes in multiple sclerosis.

BACKGROUND: Assessment of disease impact in multiple sclerosis (MS) is usually driven by information obtained directly from patients using patient-reported outcomes. However, when patients' response in longitudinal studies is less reliable or missing, proxy respondents may be used. OBJECTIVE: The objective of this paper is to evaluate whether long-term patient scores can be reliably estimated using scores obtained from proxies. METHODS: Baseline, six-month and two-year data were collected from 155 patients and proxies on the physical scale of the Multiple Sclerosis Impact Scale (MSIS-29). Linear regression analyses were performed with the patient two-year scores as outcome, proxy two-year scores as predictor and other variables that could contribute to a better prediction of the patient follow-up score. RESULTS: The patient follow-up score could be predicted rather accurately (R(2) = 0.74) using the patient baseline score and the proxy follow-up score. The correlation between observed and predicted scores was 0.86. The model performed well in different follow-up durations and even better in an external cohort. CONCLUSION: A simple model of a constant value (intercept), the patient baseline score and the proxy follow-up score can predict patients' follow-up score on the physical impact of MS.

Quantifying progression of multiple sclerosis via classification of depth videos.

This paper presents new learning-based techniques for measuring disease progression in Multiple Sclerosis (MS) patients. Our system aims to augment conventional neurological examinations by adding quantitative evidence of disease progression. An off-the-shelf depth camera is used to image the patient at the examination, during which he/she is asked to perform carefully selected movements. Our algorithms then automatically analyze the videos, assessing the quality of each movement and classifying them as healthy or non-healthy. Our contribution is three-fold: We i) introduce ensembles of randomized SVM classifiers and compare them with decision forests on the task of depth video classification; ii) demonstrate automatic selection of discriminative landmarks in the depth videos, showing their clinical relevance; iii) validate our classification algorithms quantitatively on a new dataset of 1041 videos of both MS patients and healthy volunteers. We achieve average Dice scores well in excess of the 80% mark, confirming the validity of our approach in practical applications. Our results suggest that this technique could be fruitful for depth-camera supported clinical assessments for a range of conditions.

Molecular mechanism underlying the impact of vitamin D on disease activity of MS.

OBJECTIVE: Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D. METHODS: This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs). RESULTS: The number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene-gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b. INTERPRETATION: Here, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.

The clinical meaning of walking speed as measured by the timed 25-foot walk in patients with multiple sclerosis.

IMPORTANCE: Walking impairment, a common clinical manifestation of multiple sclerosis (MS), is often measured in clinical practice and clinical trials using the Timed 25-Foot Walk (T25-FW). OBJECTIVE: To evaluate the relationship between walking speed measured by the T25-FW and the Physical Component Summary (PCS) score of the 36-Item Short Form Health Survey (SF-36) to better understand the clinical meaning of T25-FW walking speed in MS. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed data from 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis [AFFIRM], Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing-Remitting Multiple Sclerosis [SENTINEL], and International MS Secondary Progressive Avonex Controlled Trial [IMPACT]) that included T25-FW and SF-36 scores as outcomes in patients with MS. Patients had secondary-progressive MS and an Expanded Disability Status Scale score of 3.5 to 6.5 or relapsing-remitting MS and an Expanded Disability Status Scale score of 0 to 5.0. MAIN OUTCOMES AND MEASURES: We used Spearman rank correlation and Pearson product moment correlation (r ) and descriptive statistics to evaluate retrospectively the relationship between the SF-36 PCS score and T25-FW walking speed at baseline and the 2-year changes from baseline. RESULTS: Among all 2549 patients from the 3 trials, walking speed and SF-36 PCS score at baseline were significantly correlated (n = 2333; r = 0.48; P < .001). In placebo-treated patients at 2 years, the percentage of change from baseline in walking speed was significantly correlated with the change from baseline in SF-36 PCS score (r = 0.35; P < .001). Significant correlations between the change in SF-36 PCS scores and the percentage of change in walking speed at 2 years also were observed in groups receiving active treatment (r, 0.13-0.28; P ≤ .005). Among placebo-treated patients, 27.5% had a clinically meaningful worsening (≥ 5-point decrease) in SF-36 PCS scores during the 2 years. Walking speed declined by 21.8% in these patients after 2 years, but only by 5.4% in those without worsening of SF-36 PCS scores. CONCLUSIONS AND RELEVANCE: In patients with MS, walking speed measured using the T25-FW correlated with SF-36 PCS scores such that a decline in walking speed of 20% to 25% corresponded to a clinically meaningful worsening of SF-36 PCS scores. A 20% to 25% decline in walking speed may be a clinically meaningful threshold for defining worsening using the T25-FW in MS clinical trials and for monitoring patients in clinical settings.

Multiple sclerosis: current knowledge and future outlook.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity. Our understanding of the pathophysiology of MS has deepened considerably in recent years, resulting in different therapies to modify the disease course. Furthermore, several drugs have lately shown efficacy in phase III studies and their approval is expected in the near future. As treatment options expand, a future challenge will be to find the optimal treatment for the individual patient. SUMMARY: This mini-review gives an overview of the current knowledge of MS with emphasis on the latest diagnostic criteria and both current and upcoming treatment options. Key Messages: Treatment of MS changes rapidly as the knowledge and therapeutic options in MS expand. Clinical Impact: Diagnosis of MS is based on McDonald criteria. MS therapy can be divided into relapse, disease-modifying and symptomatic treatment. Relapses are commonly treated with intravenous methylprednisolone. First-line therapy consists of either interferon-ß, glatiramer acetate or teriflunomide. In general, agents used as escalation therapies (natalizumab, fingolimod and mitoxantrone) are more potent than the agents used for first-line therapy; however, these have potentially serious side effects and should be used with care.

Disruption of structural and functional networks in long-standing multiple sclerosis.

Both gray matter atrophy and disruption of functional networks are important predictors for physical disability and cognitive impairment in multiple sclerosis (MS), yet their relationship is poorly understood. Graph theory provides a modality invariant framework to analyze patterns of gray matter morphology and functional coactivation. We investigated, how gray matter and functional networks were affected within the same MS sample and examined their interrelationship. Magnetic resonance imaging and magnetoencephalography (MEG) were performed in 102 MS patients and 42 healthy controls. Gray matter networks were computed at the group-level based on cortical thickness correlations between 78 regions across subjects. MEG functional networks were computed at the subject level based on the phase-lag index between time-series of regions in source-space. In MS patients, we found a more regular network organization for structural covariance networks and for functional networks in the theta band, whereas we found a more random network organization for functional networks in the alpha2 band. Correlation analysis revealed a positive association between covariation in thickness and functional connectivity in especially the theta band in MS patients, and these results could not be explained by simple regional gray matter thickness measurements. This study is a first multimodal graph analysis in a sample of MS patients, and our results suggest that a disruption of gray matter network topology is important to understand alterations in functional connectivity in MS as regional gray matter fails to take into account the inherent connectivity structure of the brain.

Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study.

OBJECTIVES: Report long-term safety and effectiveness of natalizumab over 240 weeks in the prospective, observational, open-label Safety of TYSABRI Re-dosing and Treatment (STRATA) Study. METHODS: Patients (N = 1,094) previously enrolled in natalizumab multiple sclerosis clinical trials received natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed. RESULTS: At data cutoff (February 9, 2012), natalizumab exposure was 3,460 patient-years; a median of 56 (range 1-70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with natalizumab's known profile. Upon natalizumab re-exposure, rates of anti-natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among patients with 1 to 2 prior natalizumab doses. Patients originally randomized to placebo/another disease-modifying therapy vs natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. Patients initially randomized to natalizumab had lower annualized relapse rates over 240 weeks. CONCLUSIONS: Serious adverse events were consistent with natalizumab's known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of natalizumab treatment are consistent with its known efficacy profile. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in patients with relapsing-remitting multiple sclerosis, natalizumab stabilizes EDSS scores, decreases relapse rates, and is associated with an increased risk of progressive multifocal leukoencephalopathy.

A computer-based screening method for distress in patients with multiple sclerosis: a feasibility study.

BACKGROUND: In multiple sclerosis (MS) patients, symptoms of anxiety, depression, pain, and cognitive impairment are highly prevalent and contribute to lower wellbeing. As these physical and psychological symptoms of distress often stay unnoticed, regular screening could offer possibilities to identify and refer impaired patients to appropriate care. OBJECTIVE: The aim of our study was to pilot a new computer-based method in 43 MS patients to efficiently screen for a variety of psychological and physical symptoms of distress. METHODS: Data on feasibility and psychological and physical distress (anxiety, depression, fatigue, physical disability, cognitive functioning) were collected via a touch screen computer. Referral to psychosocial care and rehabilitation was retrospectively checked. RESULTS: The results demonstrated that most patients (35/40, 88%) considered the screening meaningful and the system easily usable (37/40, 93%). Average completion time of the screening was below 8 minutes. Many patients (35/40, 88%) had elevated distress levels, of whom the majority was referred. CONCLUSIONS: These findings imply that computer-based screening for MS-related distress incorporated in clinical care is feasible and aids to identify psychological or physical needs. A randomized controlled trial with follow-up should address whether this screening method could be more effective than routine care, and whether it can improve costs and efficiency of care.

Defining the clinical course of multiple sclerosis: the 2013 revisions.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

Do patient and proxy agree? Long-term changes in multiple sclerosis physical impact and walking ability on patient-reported outcome scales.

BACKGROUND: Patient-reported outcome scales (PROs) are useful in monitoring changes in multiple sclerosis (MS) over time. Although these scales are reliable and valid measures in longitudinal studies in MS patients, it is unknown what the impact is when obtaining longitudinal data from proxies. OBJECTIVE: The objective of this paper is to compare longitudinal changes in patient and proxy responses on PROs assessing physical impact of MS and walking ability. METHODS: In a prospective observational study, data on the Multiple Sclerosis Impact Scale (MSIS-29 physical) and Multiple Sclerosis Walking Scale (MSWS-12) were obtained from 137 patient-proxy couples at baseline and at two-year follow-up. Demographic and disease-related variables explaining agreement or disagreement between patients and proxies were investigated using linear regression analyses. RESULTS: Full agreement was found in 56% (MSIS) and 62% (MSWS) of the patient-proxy couples. Complete disagreement was very rare for both scales (2% MSIS, 5% MSWS). When patients were more positive than proxies, a higher age, longer disease duration, longer patient-proxy relationship and increased levels of depression, anxiety and caregiver burden in proxies were observed. CONCLUSION: In the majority of the patient-proxy couples there was agreement. Proxies can serve as a valuable source of information, but caution remains essential when using scores from proxies.

Morphological features of MS lesions on FLAIR* at 7 T and their relation to patient characteristics.

Recently, a new MRI technique was developed at 3 Tesla (T), called fluid attenuated inversion recovery* (FLAIR*). In this study, we implemented FLAIR* in an existing MS cohort at 7 T, to investigate whether we could corroborate results of previous 7 T studies that introduced specific MS lesion characteristics. Furthermore, we aimed to investigate the meaning of these lesion characteristics by relating them to clinical characteristics of the MS patient. Three-dimensional FLAIR and T2*-weighted images of 33 MS patients and 7 healthy controls were fused into FLAIR* images. Lesion type, signal intensity and morphology were analysed on FLAIR*, side-by-side with the original FLAIR and T2*, and correlated with clinical characteristics using Spearman's rho. Three morphological features of MS lesions were visualised: (1) central vessel (CV) within lesions, present in 78 % of total MS lesions; (2) hypointense rims around MS lesions, present in eight patients; (3) FLAIR* lesions that were hypointense at T2*, present in 13 patients. The presence of hypointense (rims around) lesions was not related to clinical characteristics. The simultaneous presence of rimlike lesions and hypointense lesions within MS patients was significantly correlated (ρ = 0.52, P < 0.01). We conclude that the implementation of the new MRI technique FLAIR* at ultra-high-field 7 T combines and corroborates the results of preceding 7 T research, by showing three morphological features of MS lesions. In addition, our study shows that these phenomena do not show a relation to patient's clinical characteristics and cannot be allocated to certain MS disease subtypes.

Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes.

BACKGROUND: Non-enhancing black holes (neBHs) are more common in multiple sclerosis (MS) patients with longer disease durations and progressive disease subtypes. OBJECTIVE: Our aim was to analyse the added value of neBHs in patients with clinically isolated syndromes (CISs) for predicting conversion to clinically definite MS (CDMS). METHODS: Patients were classified based on the presence or absence of neBHs and on the number of Barkhof-Tintoré (B-T) criteria fulfilled. Dissemination in space (DIS) was defined as the presence of at least three of the four B-T criteria. Dissemination in time (DIT)1 was defined by simultaneous presence of enhancing and non-enhancing lesions. DIT2 was defined by simultaneous presence of neBHs and T2 lesions not apparent on T1-weighted images. RESULTS: Focal T2-hyperintense brain lesions were identified in 87.7% of the 520 CIS patients, and 41.4% of them presented at least one neBH. Patients meeting DIS, DIT1, and DIT2 had a significantly higher rate of conversion to CDMS. After adjusting for DIS, only patients who fulfilled DIT1 preserved a significant increase in CDMS conversion. CONCLUSIONS: Non-enhancing black holes in CIS patients are associated with a higher risk of conversion to CDMS. However, the predictive value of this finding is lost when added to the DIS criteria.

Client-centred therapy in multiple sclerosis: more intensive diagnostic evaluation and less intensive treatment.

OBJECTIVE: Despite beneficial effects on communication and process measures, client-centred practice has been shown to result in poor functional outcomes. To examine a potential explanation for poor functional outcomes, this paper aims to assess whether in client-centred therapy more time is spent on diagnostic consultation and less time on actual treatment compared to usual care. METHOD: A multicentre cluster randomised controlled trial was performed. Thirteen hospitals and rehabilitation centres, 29 therapists and 269 outpatients with multiple sclerosis participated. Measurements included an inventory of diagnostic and treatment goals, the number of sessions, therapy duration and therapy intensity. RESULTS: In client-centred therapy, more sessions were used for diagnostic consultation (10.9% points difference, p = 0.030); the time needed to formulate the first treatment goal was longer (11.4 days difference, p = 0.041); there was a tendency towards more goals directed to diagnostic issues (0.69 goals difference, p = 0.056), spending more hours on indirect issues (1.16 h difference, p = 0.051) and towards a longer total therapy period (1.56 months difference, p = 0.058) than in usual care. CONCLUSION: Client-centred therapy resulted in more intensive diagnostic evaluation and less intensive treatment. This suggests that client-centred therapy should be adjusted towards a more proportional distribution of time devoted to diagnostic evaluation versus actual treatment.

Vitamin D as an early predictor of multiple sclerosis activity and progression.

IMPORTANCE: It remains unclear whether vitamin D insufficiency, which is common in individuals with multiple sclerosis (MS), has an adverse effect on MS outcomes. OBJECTIVES: To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis in patients with a first event suggestive of MS (clinically isolated syndrome). DESIGN, SETTING, AND PARTICIPANTS: The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a randomized trial originally designed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinically isolated syndrome. Serum 25(OH)D concentrations were measured at baseline and 6, 12, and 24 months. A total of 465 of the 468 patients randomized had at least 1 25(OH)D measurement, and 334 patients had them at both the 6- and 12-month (seasonally asynchronous) measurements. Patients were followed up for 5 years clinically and by magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: New active lesions, increased T2 lesion volume, and brain volume on magnetic resonance imaging, as well as MS relapses and disability (Expanded Disability Status Scale score). RESULTS: Higher 25(OH)D levels predicted reduced MS activity and a slower rate of progression. A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions (P < .001), 57% lower relapse rate (P = .03), 25% lower yearly increase in T2 lesion volume (P < .001), and 0.41% lower yearly loss in brain volume (P = .07) from months 12 to 60. Similar associations were found between 25(OH)D measured up to 12 months and MS activity or progression from months 24 to 60. In analyses using dichotomous 25(OH)D levels, values greater than or equal to 50 nmol/L (20 ng/mL) at up to 12 months predicted lower disability (Expanded Disability Status Scale score, -0.17; P = .004) during the subsequent 4 years. CONCLUSIONS AND RELEVANCE: Among patients with MS mainly treated with interferon beta-1b, low 25(OH)D levels early in the disease course are a strong risk factor for long-term MS activity and progression.

Patient subgroup analyses of the treatment effect of subcutaneous interferon ß-1a on development of multiple sclerosis in the randomized controlled REFLEX study.

The REFLEX study (NCT00404352) established that subcutaneous (sc) interferon (IFN) ß-1a reduced the risks of McDonald MS (2005 criteria) and clinically definite multiple sclerosis (CDMS) in patients with a first clinical demyelinating event suggestive of MS. The aim of this subgroup analysis was to assess the treatment effect of sc IFN ß-1a in patient subgroups defined by baseline disease and demographic characteristics (age, sex, use of steroids at the first event, classification of first event as mono- or multifocal, presence/absence of gadolinium-enhancing lesions, count of <9 or ≥9 T2 lesions), and by diagnosis of MS using the revised McDonald 2010 MS criteria. Patients were randomized to the serum-free formulation of IFN ß-1a, 44 µg sc three times weekly or once weekly, or placebo, for 24 months or until diagnosis of CDMS. Treatment effects of sc IFN ß-1a on McDonald 2005 MS and CDMS in the predefined subgroups were similar to effects found in the intent-to-treat population. McDonald 2010 MS was retrospectively diagnosed in 37.7 % of patients at baseline. Both regimens of sc IFN ß-1a significantly reduced the risk versus placebo of McDonald 2005 MS and CDMS, irrespective of McDonald 2010 status at baseline (risk reductions between 29 and 51 %). The effect of sc IFN ß-1a was not substantially influenced by baseline patient demographic and disease characteristics, or baseline presence/absence of McDonald 2010 MS.