Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder.

Objective: To assess the pharmacokinetics and pharmacodynamics of the long-acting terminal complement 5 (C5) inhibitor ravulizumab in adults with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) in the phase 3, open-label CHAMPION-NMOSD trial (NCT04201262). Methods: Patients aged 18 years or older received a weight-based intravenous loading dose of ravulizumab (2,400-3,000 mg) on day 1, followed by weight-based maintenance doses (3,000-3,600 mg) on day 15 and once every 8 weeks thereafter. Pharmacokinetic assessments were maximum observed concentration (Cmax, assessed at the end of the infusion) and concentration at the end of the dosing interval (Ctrough, assessed before dosing) for ravulizumab. Pharmacodynamic assessment was time-matched observed free C5 concentration in serum up to 50 weeks. Results: The pharmacokinetic/pharmacodynamic analysis included 58 patients treated with ravulizumab. Serum ravulizumab concentrations at or above the therapeutic threshold (175 µg/mL) were achieved in all patients after administration of the first dose and maintained for 50 weeks. At week 50, the mean (standard deviation) Cmax (n = 51) and Ctrough (n = 52) were 1,887.6 (411.38) and 764.4 (217.68) µg/mL, respectively. Immediate and complete terminal complement inhibition (free C5 serum concentrations < 0.5 µg/mL) was achieved by the end of the first ravulizumab infusion and sustained throughout the treatment period. No treatment-emergent antibodies to ravulizumab were observed. No impact on ravulizumab pharmacokinetics was seen for age, sex, race, hematocrit, hemoglobin, markers of renal and liver impairment, or medications commonly used by patients with NMOSD. Body weight and BMI were significant covariates of ravulizumab pharmacokinetics. Conclusions: Serum ravulizumab concentrations were maintained above the therapeutic threshold in all patients through 50 weeks of treatment. Ravulizumab achieved immediate and complete terminal complement inhibition that was sustained throughout the treatment period in adults with AQP4+ NMOSD.

Safety and efficacy of daclizumab beta in patients with relapsing multiple sclerosis in a 5-year open-label study (EXTEND): final results following early termination.

BACKGROUND: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study. METHODS: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors. RESULTS: The total safety population (N = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years. CONCLUSION: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting.

Dimethyl fumarate treatment shifts the immune environment toward an anti-inflammatory cell profile while maintaining protective humoral immunity.

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrates sustained efficacy and safety for relapsing forms of MS. Absolute lymphocyte count (ALC) is reduced initially, then stabilizes on treatment. OBJECTIVE: PROCLAIM, a 96-week, prospective, open-label, phase 3b study, assessed lymphocyte subsets and immunoglobulin (Ig) levels during 48 and 96 weeks (W) of DMF treatment. METHODS: Patients received 240 mg DMF BID. Endpoints: lymphocyte subset count changes (primary); Ig isotypes and ALC changes (secondary); adverse events and relationship between ALC changes and ARR/EDSS (exploratory); and neurofilament assessment (ad hoc). RESULTS: Of 218 patients enrolled, 158 (72%) completed the study. Median ALC decreased 39% from baseline to W96 (BL-W96), stabilizing above the lower limit of normal (baseline: 1.82 × 109/L; W48: 1.06 × 109/L; W96: 1.05 × 109/L). CD4 + and CD8 + T cells correlated highly with ALC from BL-W96 (p < 0.001). Relative to total T cells, naive CD4 + and CD8 + T cells increased, whereas CD4 + and CD8 + central and effector memory T cells decreased. Total IgA, IgG, IgM, and IgG1-4 subclass levels remained stable. Adverse event rates were similar across ALC subgroups. ARR, EDSS, and neurofilament were not correlated with ALCs. CONCLUSION: Lymphocyte decreases with DMF were maintained over treatment, yet immunoglobulins remained stable. No increase in infection incidence was observed in patients with or without lymphopenia. SUPPORT: Biogen.

Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE.

INTRODUCTION: We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported. METHODS: Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0-2 /DMF for years 3-9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed. RESULTS: Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0-2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6-0.8 and 0.9-2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was -1.32% (range -1.60% to -1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 109/L at discontinuation (n = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation. CONCLUSIONS: Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).

Real-World Safety and Effectiveness of Dimethyl Fumarate in Hispanic or Latino Patients with Multiple Sclerosis: 3-Year Results from ESTEEM.

INTRODUCTION: Compared with the non-Hispanic/non-Latino population, Hispanic/Latino patients with multiple sclerosis (MS) are reported to exhibit greater disease severity. Geographical location and genetics play a role in differences observed across Hispanic/Latino subpopulations. We evaluated real-world safety and effectiveness of dimethyl fumarate (DMF) on MS disease activity in Hispanic/Latino patients. METHODS: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating long-term safety and effectiveness of DMF in patients with MS. This interim analysis included patients newly prescribed DMF in routine practice at 394 sites globally. RESULTS: Overall, 4986 non-Hispanic/non-Latino and 98 Hispanic/Latino patients were analyzed; median (range) follow-up was 18 (2-37) months. Unadjusted annualized relapse rates (ARRs) for 12 months before DMF initiation versus 36 months post DMF initiation, respectively, were: non-Hispanic/non-Latino patients, 0.82 (95% CI 0.80-0.84) versus 0.10 (95% CI 0.09-0.10), 88% lower ARR (P < 0.0001); Hispanic/Latino patients, 0.80 (95% CI 0.65-1.00) versus 0.09 (95% CI 0.06-0.14), 89% lower ARR (P < 0.0001). In total, 28 (29%) Hispanic/Latino patients reported adverse events leading to treatment discontinuation; gastrointestinal (GI) disorders (n = 10, 10%) were the most common, consistent with the non-Hispanic/non-Latino population (8%). Median lymphocyte counts decreased by approximately 24% in the first year (vs 36% decrease in non-Hispanic/non-Latino patients) then remained stable and above the lower limit of normal in most patients. CONCLUSIONS: Relapse rates remained low in Hispanic/Latino patients, consistent with non-Hispanic/non-Latino patients. The safety profile of DMF in Hispanic/Latino patients was consistent with safety findings from the non-Hispanic/non-Latino ESTEEM population, demonstrating the real-world treatment benefit of DMF in the Hispanic/Latino patient cohort.

Real-World Safety and Effectiveness of Dimethyl Fumarate in Black or African American Patients with Multiple Sclerosis: 3-Year Results from ESTEEM.

INTRODUCTION: Black or African American (black/AA) patients with multiple sclerosis (MS) are reported to exhibit greater disease severity compared with non-black or non-AA patients. Whether differences exist in response to MS disease-modifying therapies remains uncertain, as MS clinical trials have included low numbers of non-white patients. We evaluated real-world safety and effectiveness of dimethyl fumarate (DMF) on MS disease activity in black/AA patients. METHODS: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating long-term safety and effectiveness of DMF in patients with MS. This interim analysis included patients newly prescribed DMF in routine practice at 394 sites globally. RESULTS: Overall, 4897 non-black/non-AA and 187 black/AA patients were analyzed; median (range) follow-up 18 (2-37) months. Unadjusted annualized relapse rates (ARRs) for 12 months before DMF initiation versus 36 months post DMF initiation, respectively, were: non-black/non-AA patients, 0.83 (95% CI 0.80-0.85) versus 0.10 (95% CI 0.09-0.10), 88% lower ARR (P < 0.0001); black/AA patients, 0.68 (95% CI 0.58-0.80) versus 0.07 (95% CI 0.05-0.10), 90% lower ARR (P < 0.0001). In total, 35 (19%) black/AA patients reported adverse events leading to treatment discontinuation; gastrointestinal disorders were most common (7%), consistent with non-black/non-AA patients (8%). Median lymphocyte counts decreased by 22% in the first year (vs 36% in non-black/non-AA patients), then remained stable and above lower limit of normal in most patients. CONCLUSIONS: Relapse rates remained low in black/AA patients, consistent with non-black/non-AA patients. The safety profile of DMF in black/AA patients was consistent with that in the non-black/non-AA ESTEEM population, although lymphocyte decrease was less pronounced in black/AA patients.

Effectiveness of alternative dose fingolimod for multiple sclerosis.

BACKGROUND: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. METHODS: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. RESULTS: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). CONCLUSIONS: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study.

OBJECTIVE: To characterize patients misdiagnosed with multiple sclerosis (MS). METHODS: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. RESULTS: Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. CONCLUSIONS: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance.

BACKGROUND: Dimethyl fumarate (DMF), a disease-modifying therapy for multiple sclerosis (MS), causes lymphopenia in a fraction of patients. The clinical significance of this is unknown. Several cases of progressive multifocal leukoencephalopathy in lymphopenic fumarate-treated patients have raised concerns about drug safety. Since lymphocytes contribute to MS pathology, lymphopenia may also be a biomarker for response to the drug. OBJECTIVE: The objective of this manuscript is to evaluate risk factors for DMF-induced lymphopenia and drug failure in a real-world population of MS patients. METHODS: We conducted a retrospective cohort study of 221 patients prescribed DMF at a single academic medical center between March 2013 and February 2015. RESULTS: Grade 2-3 lymphopenia developed in 17% of the total cohort and did not resolve during DMF treatment. Older age (>55), lower baseline absolute lymphocyte count and recent natalizumab exposure increased the risk of developing moderate to severe lymphopenia while on DMF. Lymphopenia was not predictive of good clinical response or of breakthrough MS activity on DMF. CONCLUSIONS: Lymphopenia develops in a significant minority of DMF-treated patients, and if grade 2 or worse, is unlikely to resolve while on the drug. Increased vigilance in lymphocyte monitoring and infection awareness is particularly warranted in older patients and those switching from natalizumab.

Predicting optimal response to B-cell depletion with rituximab in multiple sclerosis using CXCL13 index, magnetic resonance imaging and clinical measures.

BACKGROUND: B-cell depleting drugs show promise for treating multiple sclerosis. OBJECTIVE: We sought predictors of optimal response to rituximab, a B-cell depleting antibody, to help guide therapy selection. METHODS: We performed a post hoc study of 30 relapsing multiple sclerosis patients with breakthrough disease while on beta-interferon or glatiramer acetate who were treated with add-on rituximab. Standardized neurologic examinations, brain magnetic resonance imaging, and cerebrospinal fluid were obtained before and after rituximab. Tissue biomarkers were measured. Optimal responders were defined as having no evidence of disease activity. RESULTS: At baseline, optimal responders with no evidence of disease activity had higher IgG indices (P = 0.041), and higher CXCL13 indices ((cerebrospinal fluid CXCL13/serum CXCL13)/albumin index; P = 0.024), more contrast enhancing lesions (P = 0.002), better 25 foot timed walk (P = 0.001), and Expanded Disability Status Scale (P = 0.002). Rituximab treatment led to reduced cerebrospinal fluid biomarkers of tissue destruction: myelin basic protein (P = 0.046), neurofilament light chain (P < 0.001), and of inflammation (CXCL13 index; P = 0.042). CONCLUSIONS: Multiple sclerosis patients with optimal response to rituximab had higher cerebrospinal fluid IgG and CXCL13 indices, more gadolinium-enhancing lesions, and less disability at baseline. Rituximab treatment led to decreased markers of inflammation and tissue damage. If validated, these results will help identify multiple sclerosis patients who will respond optimally to B-cell depletion.

Decreased circulating miRNA levels in patients with primary progressive multiple sclerosis.

Emerging evidence underlines the importance of micro(mi)RNAs in the pathogenesis of multiple sclerosis (MS). Free-circulating miRNAs were investigated in serum from MS patients compared to controls. Statistically significant decreased levels of miR-15b, miR-23a and miR-223 were observed in MS patients (p < 0.05). Results were validated and replicated in two further independent MS populations. A direct correlation between miRNA levels and the EDSS score was determined in PPMS (p < 0.007). The generalized trend toward miRNA down-regulation could result in over-expression of target genes involved in disease pathogenesis. Circulating miRNA profiling could thus represent a new avenue to identify easily detectable disease biomarkers.

Monoclonal antibodies as disease modifying therapy in multiple sclerosis.

Multiple sclerosis (MS), a demyelinating disease of the central nervous system, was untreatable until the mid-1990s when beta-interferons and glatiramer acetate were introduced. These agents, while effective, were relatively nonspecific in action. Over the last 10 years, research has focused toward developing more targeted therapies for the disease. Monoclonal antibodies (mAbs) have been central to these efforts and many of the mAbs studied in MS have been singularly effective. We review here the 6 monoclonal antibodies that have been approved for MS or are in late-stage clinical trials, focusing on the drugs' efficacy and safety. Additionally, we review several monoclonal antibodies that were studied in MS but were found to be ineffective or even deleterious in this patient population.

CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions.

CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica.

Spinal cord ring enhancement in multiple sclerosis.

OBJECTIVE: To describe the clinical and imaging characteristics of spinal cord ring enhancement in multiple sclerosis (MS). DESIGN: Clinical case series. SETTING: Academic referral center. PATIENTS: Twenty patients with MS who had spinal cord ring enhancement were retrospectively identified from 322 cervical and thoracic spinal cord magnetic resonance imaging studies during a 3-year period. MAIN OUTCOME MEASURES: Demographics, disability, and pattern of enhancement on spinal cord and concomitant brain magnetic resonance imaging results. RESULTS: Ring enhancement was seen in 20 patients with spinal cord enhancement, most commonly in the cervical cord. Incomplete or "open" ring enhancement was the dominant pattern in 19 of the 20 patients (95%). Concurrent enhancing brain lesions were present in 14 patients, 8 of which (57%) exhibited a ring pattern of enhancement. At the time of imaging, the Expanded Disability Status Scale scores ranged from 1.0 to 7.0 (median score, 3.0). CONCLUSIONS: Ring enhancement is not an uncommon pattern for spinal cord lesions in MS, occurring with a prevalence of 6.2% (20 of 322 imaging studies). The most common pattern is incomplete ring enhancement in the cervical spinal cord. Recognition of this pattern may improve and expedite the diagnosis of MS and preclude the need for invasive diagnostic interventions.

Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis.

BACKGROUND: B cells are implicated in the pathogenesis of multiple sclerosis. A beneficial effect of B-cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear. OBJECTIVE: To determine the relationship between T and B cells and changes in cerebrospinal fluid (CSF) chemokine levels with rituximab, a monoclonal antibody that targets CD20. DESIGN: Phase 2 trial of rituximab as an add-on therapy. SETTING: The John L. Trotter Multiple Sclerosis Center, Washington University. Participants and Intervention Thirty subjects who had relapsing-remitting multiple sclerosis with clinical and magnetic resonance imaging activity despite treatment with an immunomodulatory drug received 4 weekly doses of rituximab (375 mg/m(2)). MAIN OUTCOME MEASURES: Lumbar puncture was performed before and after rituximab infusions in 26 subjects. Levels of B and T lymphocytes in the CSF were enumerated by flow cytometry, and chemoattractant levels were measured by enzyme-linked immunosorbent assay. RESULTS: After rituximab administration, CSF B-cell levels were decreased or undetectable in all subjects, and CSF T-cell levels were reduced in 21 subjects (81%). The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 levels decreased (P = .002 and P = .03, respectively). The proportional decline in CSF T-cell levels correlated with the proportional decrease in CXCL13 levels (r = 0.45; P = .03), suggesting a possible relationship. The CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment. CONCLUSIONS: In subjects with multiple sclerosis, B cells are critical for T-cell trafficking into the central nervous system and may alter the process by influencing chemokine production within the central nervous system.

Cerebrospinal fluid progranulin levels in patients with different multiple sclerosis subtypes.

Progranulin has recently attracted attention due to the discovery of mutations in its encoding gene (GRN) in several cases of frontotemporal lobar degeneration, but also for a possible role in inflammatory processes. In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. Progranulin cerebrospinal fluid (CSF) levels were evaluated in 55 patients with multiple sclerosis (MS) as well as in 35 subjects with non-inflammatory neurological diseases (NIND), 7 individuals with other inflammatory neurological disease (OIND) and 8 controls (CON), matched for ethnic background, gender and age. No statistically significant differences were found in patients compared with either NIND, OIND or CON (P>0.05), even stratifying according to disease subtype or gender. A positive correlation between progranulin CSF levels and age was observed in patients (rho=0.29, P=0.03). According to these data, progranulin does not likely play a major role in the pathogenesis of MS.

Candidate gene analysis of selectin cluster in patients with multiple sclerosis.

Three single nucleotide polymorphisms (SNPs) with a potential impact on the function of selectins (rs6133, rs4987310 and rs5368 substitutions localized in the coding regions of P-sel, L-sel and E-sel, respectively) were analyzed in an Italian population of 165 patients with multiple sclerosis (MS) as compared with 149 controls and in a replication American population of Caucasian descent consisting of 122 patients and 50 controls. No significant differences in either allelic or genotypic frequency in all the SNPs tested were found in the Italian population. A tendency to an increased frequency of the rs6133 T allele was observed in the American population, but applying the Bonferroni correction the significance threshold was not reached. Haploview analysis demonstrated that rs4987310 and rs5368 markers are in strong LD (D' = 0.97) in both populations. Combining the two SNPs, we found no difference in haplotype distribution in patients compared with controls, either in Italian or in American population. Despite the fact that selectins play a role in the pathogenesis of MS and their encoding genes are located in regions associated with the disease, the selectin gene cluster studied likely does not influence the susceptibility to MS in Caucasians.

A role for functional classification in the early identification of prognostic factors in ALS.

The aim of this study was to determine if the interval between onset of symptoms to initial electrodiagnostic studies indicates disease progression in amyotrophic lateral sclerosis (ALS). Fifty consecutive patients referred to our neurophysiology laboratory with clinical evidence of ALS were divided into two groups by outcome scores on the ALS Functional Rating Scale (ALSFRS) using 26 as a cut-off. Our results, which showed a median of four months (range 2-24 months) duration to initial electrodiagnostics for Group I (ALSFRS scores below 26) versus 10 months (range 1-24 months) for Group II (p = 0.02), suggest this measure is a marker of disease progression in ALS.