Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5-6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS. METHODS: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose. RESULTS: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab. CONCLUSION: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5-6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

The clinical and cost impact of switching to fingolimod versus other first line injectable disease-modifying therapies in patients with relapsing multiple sclerosis.

BACKGROUND: There is limited evidence on the effectiveness and healthcare costs of switching to fingolimod versus another first line injectable therapy (FLIT) in patients with relapsing multiple sclerosis (RMS) who have already been treated with FLIT. OBJECTIVE: The objectives of the study were to assess the annualized relapse rate (ARR), socio-demographic and clinical characteristics, persistence and adherence rates, healthcare resource utilization and cost among patients with RMS who either switch to fingolimod or another FLIT in routine clinical practice. METHODS: A multicenter, observational, retrospective chart review was conducted across eight clinics in Canada between 1 May 2011 and 30 June 2013. The data was collected from two cohorts: patients who switched to fingolimod and patients who switched to FLIT from a previous FLIT. RESULTS AND CONCLUSIONS: A total of 124 patients were included in the study: 82 and 42 switched to fingolimod and FLIT, respectively. There were no significant differences in the patient characteristics at the date of switch except for number of previous disease-modifying therapies (DMTs) which was higher in the fingolimod cohort (fingolimod: 1.52; FLIT: 1.10, p < .001). The ARR during the first year of switching was numerically higher in the FLIT cohort compared to the fingolimod cohort (FLIT: 0.9 [95% CI 0.3-1.6]; fingolimod: 0.3 [95% CI 0.1-0.5]). The negative binomial model adjusted for the number of previous DMTs confirmed a statistically significant difference in ARR between the fingolimod and FLIT cohorts at 12 months of follow-up (p = .012). In the fingolimod cohort, 20.7% of patients experienced at least one relapse compared to 38.1% in the FLIT cohort. In both groups, a high proportion of patients (>90%) showed good treatment adherence (≥80% of prescribed doses).

Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

BACKGROUND AND PURPOSE: Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary objective was to compare signal intensity differences between ionic and nonionic linear gadolinium-based contrast agents. MATERIALS AND METHODS: Subjects with secondary-progressive MS originally enrolled in a multicenter clinical trial were studied retrospectively. Eighty subjects (high-exposure cohort) received 9 linear gadolinium-based contrast agent administrations (30 nonionic/50 ionic) between week -4 and year 1 and a tenth administration by year 2. One hundred fifteen subjects (low-exposure cohort) received 2 administrations (40 nonionic/75 ionic) between week -4 and year 1 and a third administration by year 2. Signal intensities were measured on unenhanced T1WIs by placing sample-points on the dentate nucleus, globus pallidus, caudate, thalamus, pons, and white matter, and they were normalized using the following ratios: dentate/pons, globus pallidus/white matter, caudate/white matter, and thalamus/white matter. RESULTS: Between week -4 and year 1, subjects in the high-exposure cohort showed increased signal intensity ratios in all regions (P < .01), while the low-exposure cohort showed only an increase in the dentate nucleus (P = .003). Between years 1 and 2, when both cohorts received only 1 additional gadolinium-based contrast agent, no significant changes were observed. In the high-exposure cohort, significantly higher changes in signal intensity ratios were observed in subjects receiving linear nonionic than in those receiving linear ionic gadolinium-based contrast agents. CONCLUSIONS: Hyperintensity in deep brain structures from gadolinium deposition is related to the number of doses and the type of linear gadolinium-based contrast agent (nonionic greater than ionic) administration.

Progressive multiple sclerosis exhibits decreasing glutamate and glutamine over two years.

BACKGROUND: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial. OBJECTIVE: To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS). METHODS: Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N-acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel. RESULTS: Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate -4.2% (-6.2% to -2.2%, p < 10(-4)), glutamine -7.3% (-11.8% to -2.9%, p = 0.003), and glutamate+glutamine -5.2% (-7.6% to -2.8%, p < 10(-4)). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures. CONCLUSIONS: The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression.

A randomized trial of teriflunomide added to glatiramer acetate in relapsing multiple sclerosis.

BACKGROUND: Teriflunomide is a once-daily oral immunomodulator for the treatment of relapsing-remitting MS. OBJECTIVE: To evaluate the safety and tolerability of teriflunomide as add-on therapy to a stable dose of glatiramer acetate (GA) in patients with relapsing forms of MS (RMS). METHODS: Phase II, randomized, double-blind, add-on, placebo-controlled study. The primary objective was to assess safety and tolerability; secondary objectives were to evaluate effects of treatment on disease activity assessed by MRI and relapse. RESULTS: Patients with RMS on GA (N = 123) were randomized 1:1:1 to receive teriflunomide 14 mg (n = 40), 7 mg (n = 42), or placebo (n = 41) for 24 weeks; 96 patients entered the 24-week extension, remaining on original treatment allocation. Teriflunomide was well tolerated over 48 weeks. The frequency of adverse events (AEs) was low across all groups; 5 (12.2%), 3 (7.1%), and 2 (5.0%) patients in the 14 mg, 7 mg, and placebo groups, respectively, discontinued treatment due to AEs. Teriflunomide reduced the number of T1-Gd lesions vs placebo (14 mg: 46.6% relative reduction, p = 0.1931; 7 mg: 64.0%: relative reduction, p = 0.0306). CONCLUSIONS: Teriflunomide added to stable-dose GA had acceptable safety and tolerability, and reduced some MRI markers of disease activity compared with GA alone. NCT00475865 (core study); NCT00811395 (extension).

Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT.

OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). METHODS: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 µg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. RESULTS: Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms. CONCLUSIONS: These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS.

Treatment options for patients with multiple sclerosis who have a suboptimal response to interferon-ß therapy.

BACKGROUND AND PURPOSE: Although the first-line disease-modifying therapies (DMTs) interferon beta and glatiramer acetate have a favourable benefit-to-risk profile, they are only partially effective for treating relapsing-remitting multiple sclerosis (RRMS). The optimization of treatment in patients who do not show a maximum response to first-line therapy is critical for achieving the best long-term outcomes. Treatment strategies for patients with a suboptimal response include switching to another first-line DMT or a second-line DMT. Natalizumab and fingolimod are approved for RRMS with high disease activity in the European Union and Canada. METHODS: A comprehensive literature search for articles published between 1990 and April 2012 was undertaken. RESULTS: This review discusses key clinical and safety data for fingolimod and natalizumab, particularly in the patient subgroups for whom these treatments are approved. Benefit-to-risk profiles, including first-dose cardiovascular effects associated with fingolimod and the risk of progressive multifocal encephalopathy with natalizumab, are discussed. CONCLUSION: A descriptive comparison of fingolimod and natalizumab is provided in the context of the decision-making process of how and when to switch patients who have a suboptimal response to first-line therapy.

Cognitive change and neuroimaging following immunoablative therapy and hematopoietic stem cell transplantation in multiple sclerosis: A pilot study.

BACKGROUND: Individuals with MS undergoing immunoablative therapy and hematopoietic stem cell transplantation (HSCT) show substantial decrease in brain volume over 2.4 months, presumably from chemotoxic effects, although other mechanisms have also been postulated. OBJECTIVE: We examined whether volume loss was accompanied by a concomitant decrease in cognition. White and gray matter volumes, and the effect of stem cell dosage were considered. METHODS: Seven individuals with rapidly progressing MS and poor prognosis underwent high dose immunosuppression and autologous HSCT. Neuropsychological testing and MRI scans were performed at baseline, 2 and 24 months post-procedure. RESULTS: Cognitive impairment was noted at all times in most participants. Median decline of 1.39% in total brain volume was noted 2 months post-HSCT. By 24 months a further decline of 1.65% was noted. At 2 months significant decline was observed for areas of executive functioning. At 24 months almost no significant declines were noted. No significant correlations were found between cognitive decline and change in imaging variables or stem cell dosage. CONCLUSIONS: Cognition changed in the early period following treatment but with little apparent relationship to volume changes. With temporal distance from the HSCT procedure, cognition returned to baseline levels. With the caution of a very small sample, preliminary results suggest that immunoablation and HSCT may have no lasting deleterious effects on cognition.

Teriflunomide added to interferon-ß in relapsing multiple sclerosis: a randomized phase II trial.

OBJECTIVE: To evaluate teriflunomide as add-on therapy to ongoing stable-dosed interferon-ß (IFNß) in patients with relapsing forms of multiple sclerosis (RMS). METHODS: A total of 118 patients with RMS were randomly assigned 1:1:1 to receive oral placebo or teriflunomide, 7 or 14 mg, once daily for 24 weeks; 86 patients entered the 24-week extension. The primary objective was to evaluate safety; secondary objectives were to evaluate the effects of treatment on disease activity assessed by MRI and relapse rate. RESULTS: Teriflunomide was well tolerated with a low and similar incidence of treatment-emergent adverse events (TEAEs) across the 3 groups; TEAEs led to treatment discontinuation of 4.9%, 8.1%, and 7.9% of patients in the placebo, 7-mg, and 14-mg groups, respectively. The number of gadolinium-enhancing T1 (T1-Gd) lesions was reduced in both teriflunomide groups, with relative risk reductions (RRRs) of 84.6% (p = 0.0005) and 82.8% (p < 0.0001) for 7 and 14 mg, respectively, compared with IFNß alone at 48 weeks. T1-Gd lesion volume was also reduced in the 7-mg group (RRR 72.1%, p = 0.1104) and 14-mg group (RRR 70.6%, p = 0.0154). A trend toward dose-dependent reduction in annualized relapse rate was also noted (RRRs 32.6% [p = 0.4355] and 57.9% [p = 0.1005] for 7 and 14 mg, respectively). CONCLUSION: Teriflunomide as add-on therapy to IFNß had acceptable safety and tolerability and reduced MRI disease activity compared with IFNß alone. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that teriflunomide, 7 and 14 mg, added to IFNß, is safe. The T1-Gd lesion burden was significantly reduced with both teriflunomide doses.

A prospective, randomized, controlled trial of autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: a position paper.

BACKGROUND: Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage. OBJECTIVES: An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. CONCLUSIONS: Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.

Detecting cognitive fatigue in multiple sclerosis: method matters.

BACKGROUND: Fatigue is a frequently reported and debilitating symptom in multiple sclerosis (MS). Cognitive fatigue (CF) can be defined as decreased performance with sustained cognitive effort. The effectiveness of the Paced Auditory Serial Addition Task (PASAT) and the Computerized Test of Information Processing (CTIP) at detecting CF was examined, as was the impact of methodology. Subjective fatigue was measured using the Fatigue Impact Scale (FIS). The relationship between objective and subjective fatigue was examined. METHODS: 70 MS and 72 healthy controls (HC) completed the PASAT (3″ and 2″), CTIP, and FIS as part of a larger battery. RESULTS: The MS and HCs performed worse on cognitively demanding tasks. Depending on methodology, PASAT performance varied between groups at the 3″ inter-stimulus interval (ISI) and the MS group showed greater susceptibility to CF as their ability to meet task demands declined as the task progressed. CTIP performance for both groups varied differently over time depending on task. The relationship between subjective and objective measures of fatigue varied depending on methodology, with PASAT generally correlating well with the Cognitive Dimension of the FIS. CONCLUSIONS: The PASAT is a sensitive measure of CF in MS. Additional information is obtained with different scoring methods, with percent dyad scoring method being most sensitive to CF. The ability to detect a relationship between objective and subjective measures varied with methodology.

Activation patterns in multiple sclerosis on the Computerized Tests of Information Processing.

RATIONALE: Multiple sclerosis (MS) patients exhibit cognitive deficits that negatively impact quality of life. The Relative Consequence Model suggests that problems with information processing speed (IPS) may be the basis for many of these cognitive difficulties. OBJECTIVE: To investigate, with functional magnetic resonance imaging (fMRI), if an IPS task (the Computerized Test of Information Processing (CTIP)) would reveal neurophysiological differences between MS patients and matched controls. METHODS: Performance and neural activation were investigated in twelve cognitively impaired MS patients and 12 matched controls as each performed the CTIP. The CTIP measures reaction time (RT) and errors on three tasks (simple RT, choice RT and semantic search RT) with increasing cognitive demands. RESULTS: Participants demonstrated increased RT with increased task complexity. Patients showed longer RTs for the choice RT condition than controls but the pattern of performance across tasks did not vary between groups. Errors were not significantly different between groups. Imaging results for both the choice and the semantic search conditions revealed significant differences between groups involving a compensatory increase in activation in MS participants compared to controls in prefrontal cortex and right temporal gyri. However, there were also areas of decreased activity in MS participants when compared with controls in left temporal gyri. CONCLUSIONS: Significantly different neural activation patterns between MS patients and controls were associated with IPS, as measured by the CTIP.

Predictive nature of IgM anti-α-glucose serum biomarker for relapse activity and EDSS progression in CIS patients: a BENEFIT study analysis.

BACKGROUND: Higher serum levels of at least one of a panel of four α-glucose IgM antibodies (gMS-Classifier1) in clinically isolated syndrome (CIS) patients are associated with imminent early relapse within 2 years. OBJECTIVE: The objective of this study was to determine the prognostic value of gMS-Classifier1 in a large study cohort of CIS patients. METHODS: The BEtaseron(®) in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) 5-year study was designed to evaluate the impact of early versus delayed interferon-ß-1b (IFNß-1b; Betaseron(®)) treatment in patients with a first event suggestive of multiple sclerosis (MS). Patients (n = 258, 61% of total) with a minimum of 2 ml baseline serum were eligible for the biomarker study. gMS-Classifier1 antibodies' panel (anti-GAGA2, anti-GAGA3, anti-GAGA4 and anti-GAGA6) levels were measured blinded to clinical data. Subjects were classified as either 'positive' or 'negative' according to a classification rule. RESULTS: gMS-Classifier1 was not predictive for the time to clinically definite MS or time to MS according to the revised McDonald's criteria, but did significantly predict an increased risk for confirmed disability progression (log-rank test: p = 0.012). CONCLUSIONS: We could not confirm previous results that gMS-Classifier1 can predict early conversion to MS in CIS. However, raised titres of these antibodies may predict early disability progression in this patient population.

A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS.

OBJECTIVE: To evaluate the efficacy and safety of MBP8298 in subjects with secondary progressive multiple sclerosis (SPMS) who express human leukocyte antigen (HLA) haplotype DR2 or DR4 (DR2(+) or DR4(+)). METHODS: This multicenter randomized 2-year, double-blind, placebo-controlled study included 612 subjects with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) score of 3.5-6.5, stratified according to baseline EDSS score (3.5-5.0, or 5.5-6.5) and HLA haplotype (DR2(+) or DR4(+), or DR2(-)/DR4(-)). Upon entry of 100 DR2(-)/DR4(-) subjects, further study enrollment was limited to DR2(+) or DR4(+) subjects. Subjects were randomly assigned to either 500 mg MBP8298 or placebo, given by IV injection once every 6 months for 2 years. The primary outcome measure was time to progression by ≥1.0 EDSS point (or 0.5 point if baseline EDSS was 5.5 or higher), confirmed 6 months later. Secondary outcomes included mean change in EDSS, mean change in Multiple Sclerosis Functional Composite, MRI changes, annualized relapse rate, and quality of life. RESULTS: There were no significant differences between treatment groups in either the primary or secondary endpoints. MBP8298 was well tolerated in all treated subjects with no safety issues identified. CONCLUSION: In the population studied, treatment with MBP8298 did not provide a clinical benefit compared to placebo. CLASSIFICATION OF EVIDENCE: This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2(+) or DR4(+).

Interferon ß-1b-neutralizing antibodies 5 years after clinically isolated syndrome.

OBJECTIVE: To determine the frequency and consequences of neutralizing antibodies (NAbs) in patients with a first event suggestive of multiple sclerosis (MS) treated with interferon ß-1b (IFNß-1b). METHODS: In the Betaseron/Betaferon in Newly Emerging MS For Initial Treatment (BENEFIT) study, patients were randomly assigned to 250 µg IFNß-1b (Betaferon) or placebo subcutaneously every other day for 2 years or until diagnosis of clinically definite MS (CDMS). Patients were then offered open-label IFNß-1b for up to 5 years. NAb status was assessed every 6 months by the myxovirus protein A induction assay. A titer >20 NU/mL was considered NAb-positive, with low (≥20-100 NU/mL), medium (≥100-400 NU/mL), and high (≥400 NU/mL) titer categories. Here we examine early-treated patients, who received IFNß-1b for up to 5 years. RESULTS: NAbs were measured in 277 of 292 early-treated patients and detected at least once in 88 (31.8%) patients, with 53 (60.2%) reverting to NAb negativity by year 5. Time to CDMS, time to confirmed disability progression, and annualized relapse rate did not differ between NAb-positive and NAb-negative patients or between periods of NAb positivity vs NAb negativity within patients. Increases in newly active lesion number and T2 lesion volume and conversion to McDonald MS were associated with NAb positivity and were more pronounced with higher titers. CONCLUSIONS: Although NAb positivity was associated with increased brain MRI activity, no discernible effects on clinical outcomes were found. This finding may reflect the greater power of MRI compared with clinical outcomes to detect the treatment effects of IFNß-1b and may also result from temporal changes in NAb titers and biology.

Meaningful change in cognition in multiple sclerosis: method matters.

OBJECTIVE: To determine if different methods of evaluating cognitive change over time yield measurably different outcomes. METHODS: Twelve cognitively impaired patients with clinically definite Multiple sclerosis (10 relapsing-remitting, 2 secondary progressive) underwent neuropsychological testing (baseline, 6, 12 months). Data was analysed using: t-tests evaluating group differences on individual tests, group differences in composite scores, reliable change analyses at the level of the individual, and comparisons regarding number of tests failed at each time point. RESULTS: Group t-tests on individual tests yielded no change. When tests were grouped according to theoretical constructs, analyses revealed change in processing speed. Reliable change estimates revealed that 16% of the sample deteriorated. When change was measured with respect to the number of domains affected at each time point, 58% of the sample deteriorated on at least one subtest. CONCLUSIONS: Methodology has a significant impact on interpretation of longitudinal data. In the same group of subjects, traditional group analyses documented no change in individual test scores or change on a single composite score. Analyses of individual results documented change from 16 to 58% of the sample. Advantages and disadvantages of each method were discussed. Findings have implications for interpretation of longitudinal studies.

TLR-mediated B cell activation results in ectopic CLIP expression that promotes B cell-dependent inflammation.

Infectious pathogens produce compounds called Toll ligands that activate TLRs on lymphocytes. Acute activation triggered by certain TLRs appears to "jump start" the innate immune response, characterized by the release of inflammatory cytokines and cellular expansion. In some individuals, there is a failure to control acute inflammation, resulting in postinfectious, chronic inflammation. Susceptibility to chronic inflammation is strongly associated with an individual's MHC genes. Recent clinical trials for several autoimmune diseases characterized by chronic inflammation suggest that B lymphocyte depletion therapies dampen chronic immune activation. However, currently, there is no known mechanism that accounts for the correlation among TLR activation, MHC genetics, and a pathological role for B-lymphocytes. Our hypothesis is that TLR-activated B cells (B cells that have been polyclonally activated in the absence of antigen-specific signals) are not controlled properly by T cell-dependent B cell death, thereby causing B cell-dependent chronic inflammation. Here, we show that treatment with Toll ligands results in polyclonal B cell activation accompanied by ectopic expression of CLIP. Furthermore, by adoptively transferring purified CLIP+ B cells in syngeneic animals, we find that CLIP+ B cells induce production of TNF-α by host T cells. Finally, we demonstrate that CLIP-targeted peptide competition results in the death of polyclonally activated CLIP+ B cells.

Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis.

Anti-myelin basic protein (MBP) antibodies in pediatric-onset MS and controls were characterized. Serum samples were obtained from 94 children with MS and 106 controls. Paired CSF and serum were obtained from 25 children with MS at time of their initial episode of acute demyelinating syndrome (ADS). Complementary assays were applied across samples to evaluate the presence, and the physical binding properties, of anti-MBP antibodies. While the prevalence and titers of serum anti-MBP antibodies against both immature and mature forms of MBP were similar in children with MS and in controls, binding characteristics and formal Surface Plasmon Resonance (SPR) studies indicated surprisingly high binding affinities of all pediatric anti-MBP antibodies. Serum levels of anti-MBP antibodies correlated significantly with their CSF levels, and their presence in children with MS was associated with significantly increased risk of an acute disseminated encephalomyelitis-like initial clinical presentation. While antibodies to both immature and mature forms of MBP can be present as part of the normal pediatric humoral repertoire, these anti-myelin antibodies are of surprisingly high affinity, can access the CNS during inflammation, and have the capacity to modulate disease expression. Our findings identify an immune mechanism that could contribute to the observed heterogeneity in spectrum of clinical presentations in early-onset MS.