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Background: Overall Disability Response Score (ODRS) is a composite endpoint including Expanded Disability Status Scale, Timed 25-foot Walk, and 9-Hole Peg Test, designed to quantify both disability improvement and worsening in multiple sclerosis (MS)., Objective: To assess the sensitivity and clinical meaningfulness of ODRS using natalizumab Phase 3 data sets (AFFIRM in relapsing-remitting MS and ASCEND in secondary progressive MS)., Methods: Differences in ODRS over 96 weeks, ODRS at Week 96, and slope of ODRS change per year between natalizumab and placebo groups were analyzed. Correlation between ODRS and changes in patient-reported outcomes was also analyzed., Results: The difference (95% confidence interval (CI)) in the ODRS over 96 weeks between natalizumab and placebo groups was 0.34 (0.21-0.46) in AFFIRM ( p  < 0.001), and 0.18 (0.03-0.34) in ASCEND ( p  = 0.021). Significant differences between treatment arms were also observed in ODRS at Week 96 and in the slope of change per year in both studies. There was a significant linear correlation between ODRS at Week 96 and the change from baseline in both the physical and mental components of the 36-item Short Form Survey (SF-36) in both studies., Conclusion: This analysis supports ODRS as a sensitive and potentially clinically meaningful disability outcome measure in MS.

Objectives: Bruton's tyrosine kinase (BTK) plays a non-redundant signaling role downstream of the B-cell receptor (BCR) in B cells and the receptors for the Fc region of immunoglobulins (FcR) in myeloid cells. Here, we characterise BIIB091, a novel, potent, selective and reversible small-molecule inhibitor of BTK., Methods: BIIB091 was evaluated in vitro and in vivo in preclinical models and in phase 1 clinical trial., Results: In vitro, BIIB091 potently inhibited BTK-dependent proximal signaling and distal functional responses in both B cells and myeloid cells with IC 50 s ranging from 3 to 106 nm, including antigen presentation to T cells, a key mechanism of action thought to be underlying the efficacy of B cell-targeted therapeutics in multiple sclerosis. BIIB091 effectively sequestered tyrosine 551 in the kinase pocket by forming long-lived complexes with BTK with t 1/2 of more than 40 min, thereby preventing its phosphorylation by upstream kinases. As a key differentiating feature of BIIB091, this property explains the very potent whole blood IC 50 s of 87 and 106 nm observed with stimulated B cells and myeloid cells, respectively. In vivo , BIIB091 blocked B-cell activation, antibody production and germinal center differentiation. In phase 1 healthy volunteer trial, BIIB091 inhibited naïve and unswitched memory B-cell activation, with an in vivo IC 50 of 55 nm and without significant impact on lymphoid or myeloid cell survival after 14 days of dosing., Conclusion: Pharmacodynamic results obtained in preclinical and early clinical settings support the advancement of BIIB091 in phase 2 clinical trials., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)

Peripheral inflammation is known to trigger a mirror inflammatory response in the brain, involving brain's innate immune cells - microglia. However, the functional phenotypes, which these cells adopt in the course of peripheral inflammation, remain obscure. In vivo two-photon imaging of microglial Ca 2+ signaling as well as process motility reveals two distinct functional states of cortical microglia during a lipopolysaccharide-induced peripheral inflammation: an early "sensor state" characterized by dramatically increased intracellular Ca 2+ signaling but ramified morphology and a later "effector state" characterized by slow normalization of intracellular Ca 2+ signaling but hypertrophic morphology, substantial IL-1β production in a subset of cells as well as increased velocity of directed process extension and loss of coordination between individual processes. Thus, lipopolysaccharide-induced microglial Ca 2+ signaling might represent the central element connecting receptive and executive functions of microglia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In patients treated with dimethyl fumarate, absolute lymphocyte count decline typically occurs during the first year and then plateaus; early drops have been associated with the development of severe prolonged lymphopenia., Objective: We investigated the effect of dimethyl fumarate on absolute lymphocyte counts and CD4+/CD8+ T cells in patients with relapsing-remitting multiple sclerosis treated with dimethyl fumarate in routine practice., Methods: Lymphocyte data were collected via medical chart abstraction. Primary endpoint: change from baseline in absolute lymphocyte count and CD4+/CD8+ counts at 6-month intervals following dimethyl fumarate initiation., Results: Charts of 483 patients were abstracted and 476 patients included in the analysis. Mean baseline absolute lymphocyte count (2.23 × 10 9 /l) decreased by ∼39% (95% confidence interval: -41.1 to -37.2) by month 6 and 44% (95% confidence interval: -46.6 to -42.1) by month 12. CD4+ and CD8+ T-cell subsets strongly correlated with absolute lymphocyte count, with greater decreases from baseline to 6 months vs 6-12 months, and in CD8+ vs CD4+ T cells. Prior natalizumab was not a risk factor for lymphopenia., Conclusion: Dimethyl fumarate-associated decline in absolute lymphocyte count in the first 12 months correlated with decline in CD4+ and CD8+ T cells and was independent of prior natalizumab. Absolute lymphocyte count monitoring continues to be an effective strategy to identify patients at risk of prolonged lymphopenia., (© The Author(s) 2020.)

Objective: To examine the impact of missing data when evaluating the confirmed disability worsening (CDW) endpoint in multiple sclerosis clinical trials and explore analytical methods for handling censored participants (those with missing confirmation data)., Methods: CDW risk factors were assessed among participants with an initial disability worsening (≥ 1.0-point increase in Expanded Disability Status Scale [EDSS] score from a baseline score of ≥ 1.0; ≥ 1.5-point increase from a baseline of 0) using data from the DECIDE trial of daclizumab beta. A post-hoc simulation study was performed to evaluate three strategies for imputing confirmation status in censored participants: assume all were confirmed; assume none were confirmed (standard analytical approach); or use an observed rate multiple imputation (ORMI) approach based on treatment group and similar participant risk factors. Simulation study results were used to evaluate pre-specified analyses in DECIDE., Results: In DECIDE, larger change from baseline to initial disability worsening in EDSS score (p = 0.0003), higher baseline EDSS score (p = 0.0013), age (p = 0.004), and preceding relapse (p < 0.0001) were associated with 12-week CDW. In the simulation study, relative to the full dataset (no missing data), the strategy of assuming no censored participants were confirmed underestimated the treatment effect, and the strategy of assuming all censored participants were confirmed overestimated the treatment effect (hazard ratio 0.749 and 0.713 vs 0.733). ORMI correctly estimated treatment effect and increased study power by ~5-10% compared with the standard analytical approach., Conclusion: The ORMI approach based on CDW risk factors minimizes bias and is expected to provide the most accurate treatment effect estimate for the CDW endpoint., Competing Interests: Declaration of Competing Interest Katherine Riester is an employee of and holds stock/stock options in Biogen. Ludwig Kappos’ institution has received in the last 3 years, and used exclusively for research support: steering committee/consulting fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, and XenoPort; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi-Aventis, and Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva; license fees for Neurostatus products; and grants from Bayer HealthCare, Biogen, the European Union, Merck, Novartis, Roche, Roche Research Foundations, the Swiss Multiple Sclerosis Society, and the Swiss National Research Foundation. Krzysztof Selmaj has received consulting fees from Genzyme, Novartis, Ono, Roche, Synthon, and Teva, and speaker fees from Biogen. Stacy Lindborg is an employee of and holds stock/stock options in Biogen. Ilya Lipkovich is a former employee of IQVIA (formerly Quintiles); he performed statistical analysis as part of the contract between Biogen and IQVIA. Jacob Elkins is an employee of and holds stock/stock options in Biogen., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous real-world comparative research of MS disease modifying therapies (DMTs) in the overall population has suggested dimethyl fumarate (DMF) to be comparable to fingolimod (FTY) and more efficacious than teriflunomide (TERI) in reducing relapses. However, there is limited comparative evidence in patients switching from platform DMTs in the US. The objective of the study was to compare the annualized relapse rate (ARR) and risk of relapse in MS patients who have switched from a platform therapy to DMF, FTY, or TERI., Methods: MS patients (18-65 years old) initiating an oral DMT from June 2013 to March 2015 were identified from the Truven MarketScan ® Commercial Claims Database. The index date was the date of first oral DMT fill. Patients were required to have: continuous enrollment in the database for 12 months pre-index date and ≥3 months post-index date; ≥1 MS diagnosis over the pre-index period; discontinuation of a platform DMT with no evidence of oral or infusion DMTs over the pre-index period; and adherence to the index drug for ≥90 days. DMF patients were propensity-score matched (PSM) 3:1 to FTY and to TERI based on age, gender, region, a claims-based MS severity measure, ARR, and number of hospitalizations over the pre-index period. Patients were censored when they dropped out of the database or at the end of the study period (March 31, 2016). Post-index relapses were annualized., Results: The database included 20,311 oral DMT users. After applying the study criteria, the PSM yielded 1602:534 switch patients for the DMF-FTY matched cohort. DMF-FTY patients were well-matched on all covariates: age (mean = 44 for both), gender (28% vs. 26% male, respectively), MS severity measure (0.99 vs. 1.08), and baseline ARR (0.40 vs. 0.44). PSM yielded 833:279 switch patients for the DMF-TERI match. DMF-TERI patients were well-matched on all covariates: age (mean = 50), gender (24% vs. 25% male), MS severity measure (0.86 vs. 0.99), and baseline ARR (0.23 vs. 0.30). The standardized differences confirmed balance across all covariates for matched cohorts. The matched DMF-FTY cohorts had comparable post-index ARR (Rate Ratio [RR] = 1.07 [95% Cl: 0.861, 1.328]) and risk of relapse (Hazard Ratio [HR ]= 0.996 [95% CI: 0.803, 1.236]). Post-index ARR was significantly lower with DMF in comparison to TERI (RR = 0.667 [0.486, 0.914]). The risk of relapse was also significantly lower when switching to DMF than TERI (HR = 0.679 [0.503, 0.917])., Conclusion: In this analysis, the effectiveness profiles for those oral DMT users specifically switching from platform therapies are consistent with findings from previous research conducted among all oral DMT users, regardless of prior therapy., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: Flushing and gastrointestinal (GI) events are commonly associated with the use of delayed-release dimethyl fumarate (DMF) treatment for relapsing multiple sclerosis., Methods: PREVENT (A Multicenter, Double-Blind, Placebo-Controlled Study of Pepto-Bismol [Bismuth Subsalicylate] on Gastrointestinal Tolerability in Healthy Volunteers Receiving Oral TECFIDERA [Dimethyl Fumarate] Delayed-Release Capsules Twice Daily) is a double-blind, placebo-controlled, 8-week study that evaluated the effect of bismuth subsalicylate on DMF-related GI events. Bismuth subsalicylate 524 mg or placebo were administered 30 min before DMF (weeks 1-4). DMF was dosed twice-daily (BID) at 120 mg (week 1) and 240 mg (weeks 2-8). Using an e-diary device, participants recorded GI and flushing events on the Modified Overall Gastrointestinal Symptom Scale once daily for the preceding 24 h. The primary end point was time to first GI-related event. Secondary end points included frequency and severity of GI-related events., Findings: A total of 175 participants were enrolled (placebo, n = 87; bismuth subsalicylate, n = 88), and 17 discontinued treatment (placebo, n = 8; bismuth subsalicylate n = 9). A total of 146 participants reported ≥1 GI event: placebo, n = 72 (82.8%); and bismuth subsalicylate, n = 74 (84.1%). There was no statistical difference in risk of a GI event between the groups (P = 0.8292). Mean (SD) time from DMF initiation to first GI event was similar: placebo, 5.4 (8.73) days; and bismuth subsalicylate, 5.6 (10.87) days. Incidence of flatulence (38.6% vs 50.6%) and diarrhea (36.4% vs 48.2%) during weeks 1-4 was numerically lower in the bismuth subsalicylate group compared with the placebo group. Mean worst severity scores for flatulence (1.1 vs 1.8; P = 0.0219) and diarrhea (1.0 vs 1.6; P = 0.0500) were lower with bismuth subsalicylate than with placebo., Implications: Although coadministration of bismuth subsalicylate did not affect the occurrence of DMF-related GI events overall, it reduced the severity and incidence of flatulence and diarrhea. ClinicalTrials.gov identifier: NCT01915901., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Cognitive impairment is common in multiple sclerosis (MS), with cognitive processing speed being the most frequently affected domain., Objective: Examine the effects of daclizumab beta versus intramuscular (IM) interferon (IFN) beta-1a on cognitive processing speed as assessed by Symbol Digit Modalities Test (SDMT)., Methods: In DECIDE, patients with relapsing-remitting multiple sclerosis (RRMS) (age: 18-55 years; Expanded Disability Status Scale (EDSS) score 0-5.0) were randomized to daclizumab beta ( n = 919) or IM IFN beta-1a ( n = 922) for 96-144 weeks. SDMT was administered at baseline and at 24-week intervals., Results: At week 96, significantly greater mean improvement from baseline in SDMT was observed with daclizumab beta versus IM IFN beta-1a ( p = 0.0274). Significantly more patients treated with daclizumab beta showed clinically meaningful improvement in SDMT (increase from baseline of ⩾3 points ( p = 0.0153) or ⩾4 points ( p = 0.0366)), and significantly fewer patients showed clinically meaningful worsening (decrease from baseline of ⩾3 points ( p = 0.0103)). Odds representing risk of worsening versus stability or improvement on SDMT were significantly smaller for daclizumab beta ( p = 0.0088 (3-point threshold); p = 0.0267 (4-point threshold)). In patients completing 144 weeks of treatment, the effects of daclizumab beta were generally sustained., Conclusion: These results provide evidence for a benefit of daclizumab beta versus IM IFN beta-1a on cognitive processing speed in RRMS., Trial Registration: ClinicalTrials.gov identifier NCT01064401 (Efficacy and Safety of BIIB019 (Daclizumab High Yield Process) Versus Interferon β 1a in Participants With Relapsing-Remitting Multiple Sclerosis (DECIDE)): https://clinicaltrials.gov/ct2/show/NCT01064401 .

Background: Daclizumab beta is a humanized monoclonal antibody specific for the human interleukin-2 receptor alpha chain (CD25). In two pivotal studies in relapsing multiple sclerosis (MS), patients treated with daclizumab beta exhibited lower annualized relapse rates (ARR) when compared with placebo or with intramuscular (IM) interferon beta-1a., Objectives: To determine if the efficacy of daclizumab beta demonstrated in the phase 2 SELECT study and the phase 3 DECIDE study was consistent in patient subgroups., Methods: In the SELECT study, patients received daclizumab beta 150 or 300mg administered subcutaneously every 4 weeks for 52 weeks, and were compared with patients who received placebo. In the DECIDE study, patients received daclizumab beta 150mg administered subcutaneously every 4 weeks for 96-144 weeks, and were compared with patients who received IM interferon beta-1a 30µg. Subgroups were defined by sex, age, the number of relapses in the year before the study, disease duration, baseline disability measured by EDSS, presence of Gd-enhancing lesions, T2 hyperintense lesion volume at baseline, and previous interferon beta-1a use., Results: Treatment with daclizumab beta was associated with relative lower ARR, with 95% confidence intervals (CIs) below 1 in 13 of 15 subgroups (SELECT study) compared with placebo and in all 17 subgroups compared with interferon beta-1a (DECIDE study). In 2 subgroups in the SELECT study (patients who were older than 35 years of age or who had a disease duration of 10 or more years), the rate ratio point estimate for the ARR was in favor of daclizumab beta but the 95% CI overlapped with 1. The clinical benefits in ARR achieved with daclizumab beta treatment compared with placebo or interferon beta-1a across subgroups were similarly supported by reductions in lesion activity on magnetic resonance images (MRIs)., Conclusions: These findings suggest that treatment with daclizumab beta is consistently effective among clinically important patient subgroups and support its potential as a viable therapeutic option across the spectrum of relapsing MS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Patient-reported outcomes (PROs) provide information on treatment effects from the patient's perspective that complement outcomes on clinical measures. In DECIDE, daclizumab demonstrated superior efficacy in reducing relapses, 24-week confirmed disability progression, and brain lesions (assessed by magnetic resonance imaging [MRI]) versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis., Objective: To examine the impact of daclizumab versus interferon beta-1a on PROs in DECIDE., Methods: DECIDE was a randomized, double-blind, active-controlled, phase 3 study comparing daclizumab 150mg subcutaneous every 4 weeks with interferon beta-1a 30mcg intramuscular once weekly. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) and EuroQoL 5-Dimensions (EQ-5D) were assessed at baseline and every 24 weeks. Mean changes from baseline were analyzed using analysis of covariance models. Individual items for the MSIS-29 physical (PHYS) and psychological (PSYCH) subscales were analyzed post hoc., Results: Daclizumab treatment resulted in greater mean improvements relative to baseline in MSIS-29 PHYS and PSYCH scores starting at week 24 that persisted over 96 weeks. Mean improvements from baseline in MSIS-29 PHYS and PSYCH scores were significantly greater for daclizumab versus intramuscular interferon beta-1a at week 96. Daclizumab-treated patients showed steady improvements in EQ-5D health utility index and EQ-5D visual analog scale scores over the study period, with significantly greater improvements versus intramuscular interferon beta-1a at week 96 (p=0.0048 and p=0.0006, respectively)., Conclusions: Improvements in patient-reported physical and psychological functioning and general health status with daclizumab compared with intramuscular interferon beta-1a are consistent with outcomes on clinical and brain MRI lesion measures in DECIDE (NCT01064401)., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders., Methods: We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate., Results: The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P<0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs. <1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%)., Conclusions: Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a. (Funded by Biogen and AbbVie Biotherapeutics; DECIDE ClinicalTrials.gov number, NCT01064401.).

Objective: To assess the relationship between CD56(bright) natural killer (NK) cells and multiple sclerosis (MS) disease activity in patients with relapsing-remitting MS treated with daclizumab high-yield process (DAC HYP)., Methods: Data were from patients enrolled in a 52-week randomized, double-blind, placebo-controlled study of DAC HYP and its extension study. Assessments included relationships of CD56(bright) NK cell numbers (identified using fluorescence-activated cell sorting) at weeks 4 and 8 with the numbers of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 and the annualized relapse rate., Results: In DAC HYP-treated patients but not placebo-treated patients, the numbers of CD56(bright) NK cells increased over 52 weeks of treatment, and their numbers at weeks 4 and 8 predicted the number of new or newly enlarging T2-hyperintense lesions between weeks 24 and 52 of treatment (p ≤ 0.005 for each comparison). Similar but nonsignificant trends were observed between CD56(bright) NK cell counts and the annualized relapse rate in DAC HYP-treated patients. DAC HYP-treated patients who showed lower levels of expansion of CD56(bright) NK cells still developed fewer new or newly enlarging T2-hyperintense lesions than placebo-treated patients during the first year of treatment., Conclusions: CD56(bright) NK cells appear to mediate some of the treatment-related effects of DAC HYP, but their numbers do not account for the full effect of DAC HYP on MS-related outcomes.

Neuroinflammation is a hallmark of Alzheimer's disease (AD) both in man and in multiple mouse models, and epidemiological studies link the use of anti-inflammatory drugs with a reduced risk of developing the disease. AD-related neuroinflammation is largely mediated by microglia, the main immune cells of the central nervous system. In vitro, executive functions of microglia are regulated by intracellular Ca(2+) signals, but little is known about microglial Ca(2+) signaling in vivo. Here we analyze in vivo properties of these cells in two mouse models of AD. In both strains plaque-associated microglia had hypertrophic/amoeboid morphology and were strongly positive for markers of activation such as CD11b and CD68. Activated microglia failed to respond reliably to extracellular release of adenosine triphosphate (ATP, mimicking tissue damage) and showed an increased incidence of spontaneous intracellular Ca(2+) transients. These Ca(2+) transients required activation of ATP receptors and Ca(2+) release from the intracellular Ca(2+) stores, and were not induced by neuronal or astrocytic hyperactivity. Neuronal silencing, however, selectively increased the frequency of Ca(2+) transients in plaque-associated microglia. Thus, our in vivo data reveal substantial dysfunction of plaque-associated microglia and identify a novel Ca(2+) signal possibly triggering a Ca(2+)-dependent release of toxic species in the plaque vicinity.

Patients with highly active relapsing-remitting multiple sclerosis (RRMS) are at greater risk for disease progression and may respond differently to MS therapeutics than those with less active disease. The current post hoc analysis evaluated the effects of daclizumab high-yield process (DAC HYP) vs. placebo in patients with highly active RRMS in the SELECT study. Highly active RRMS was defined as patients with ≥2 relapses in the year before randomization and ≥1 gadolinium-enhancing (Gd(+)) lesion at baseline. Because results were similar in the DAC HYP dose groups, data from the DAC HYP arms were pooled for analysis. Treatment with DAC HYP resulted in similar effects in highly active (n = 88) and less active (n = 506) RRMS patients. DAC HYP reduced the annualized relapse rate by 50 % and 51 % in the highly active (p = 0.0394) and less active (p < 0.0001) groups vs. placebo, respectively (interaction p = 0.82). DAC HYP reduced new/newly-enlarging T2 lesions (highly active RRMS 76 % reduction, p < 0.0001; less active RRMS 73 % reduction, p < 0.0001; interaction p = 0.18), the risk of having more Gd(+) lesions (highly active RRMS 89 % reduction, p < 0.0001; less active RRMS 86 % reduction, p < 0.0001; interaction p = 0.46), and sustained disability progression (highly active RRMS 88 % reduction, p = 0.0574; less active RRMS 46 % reduction, p = 0.0383; interaction p = 0.22) vs. placebo. DAC HYP efficacy was similar across the spectrum of MS disease activity as assessed prior to treatment initiation.

Background: Daclizumab, a humanised monoclonal antibody, modulates interleukin-2 signalling by blocking the α subunit (CD25) of the interleukin-2 receptor. We assessed whether daclizumab high-yield process (HYP) would be effective when given as monotherapy for a 1 year treatment period in patients with relapsing-remitting multiple sclerosis., Methods: We did a randomised, double-blind, placebo-controlled trial at 76 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, Turkey, and the UK between Feb 15, 2008, and May 14, 2010. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1), via a central interactive voice response system, to subcutaneous injections of daclizumab HYP 150 mg or 300 mg, or placebo, every 4 weeks for 52 weeks. Patients and study personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug for injection, but had no interaction with the patient. The primary endpoint was annualised relapse rate. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00390221., Findings: 204 patients were assigned to receive placebo, 208 to daclizumab HYP 150 mg, and 209 to daclizumab HYP 300 mg, of whom 188 (92%), 192 (92%), and 197 (94%), respectively, completed follow-up to week 52. The annualised relapse rate was lower for patients given daclizumab HYP 150 mg (0·21, 95% CI 0·16-0·29; 54% reduction, 95% CI 33-68%; p<0·0001) or 300 mg (0·23, 0·17-0·31, 50% reduction, 28-65%; p=0·00015) than for those given placebo (0·46, 0·37-0·57). More patients were relapse free in the daclizumab HYP 150 mg (81%) and 300 mg (80%) groups than in the placebo group (64%; p<0·0001 in the 150 mg group and p=0·0003 in the 300 mg group). 12 (6%) patients in the placebo group, 15 (7%) of those in the daclizumab 150 mg group, and 19 (9%) in the 300 mg group had serious adverse events excluding multiple sclerosis relapse. One patient given daclizumab HYP 150 mg who was recovering from a serious rash died because of local complication of a psoas abscess., Interpretation: Subcutaneous daclizumab HYP administered every 4 weeks led to clinically important effects on multiple sclerosis disease activity during 1 year of treatment. Our findings support the potential for daclizumab HYP to offer an additional treatment option for relapsing-remitting disease., Funding: Biogen Idec and AbbVie Biotherapeutics Inc., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The objective of this study was to evaluate whether interleukin-2 (IL-2) receptor expression on CD56(bright) natural killer (NK) cells predicted CD56(bright) NK cell expansion and therapeutic response to daclizumab (DAC) in multiple sclerosis (MS)., Methods: DAC exposure, CD56(bright) NK cell counts, IL-2 receptor alpha (CD25) and beta (CD122) subunits, and new or enlarged lesions on brain MRI were measured in 64 subjects in a pharmacokinetic/pharmacodynamic substudy of the phase 2 CHOICE trial at multiple time points. Peripheral blood mononuclear cell (PBMC) samples were obtained from healthy subjects to assess the relationship among DAC treatment, intermediate affinity IL-2 signaling, and CD56(bright) NK cell expansion., Results: Increased CD56(bright) NK cell counts in DAC/interferon beta (IFNβ)-treated subjects were observed by day 14, the first post-dosing time point (mean [SD] ln{CD56(bright) NK cell count}: DAC high/IFNβ, 2.01 [1.25]; DAC low/IFNβ, 2.29 [1.06]; placebo/IFNβ, 1.01 [1.03]; adjusted p = 0.003), and persisted throughout the treatment period. Higher DAC dose predicted a faster rate of CD56(bright) NK cell expansion (p < 0.001), but individual subjects' increases in CD56(bright) NK cells from baseline levels were only weakly correlated with DAC exposure (r(2) = 0.167). Higher expression of the intermediate-affinity IL-2 receptor subunit (CD122) on CD56(bright) NK cells at baseline predicted fewer new gadolinium-enhanced (Gd+) lesions during the treatment period (1.77 vs. 0.62 adjusted mean new Gd+ lesions during weeks 8-24, lowest vs. highest quartile of percentage CD122(+) CD56(bright) NK cells; p = 0.033) and a greater increase in CD56(bright) NK cell counts at the end of DAC dosing (p = 0.029)., Conclusion: CD56(bright) NK cell expansion after DAC treatment appears to reflect individual differences in the capacity for intermediate-affinity IL-2 signaling and could provide a basis for predicting clinical response to DAC in MS.

Objective: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) shares immunologic features with multiple sclerosis (MS). Because IM interferon beta-1a (IM IFNbeta-1a) is an effective and safe treatment for MS, we conducted a dose-ranging efficacy study of IFNbeta-1a in patients with CIDP., Methods: Adults with IV immunoglobulin (IVIg)-dependent CIDP (n = 67) were enrolled in this 32-week double-blind trial and randomized to IM IFNbeta-1a. Patients received 30 microg once weekly plus placebo (n = 12), IM IFNbeta-1a 60 microg once weekly plus placebo (n = 11), IM IFNbeta-1a 30 microg twice weekly (n = 11), IM IFNbeta-1a 60 microg twice weekly (n = 11), or placebo twice weekly (n = 22). Participants were maintained on IVIg through week 16, when IVIg was discontinued. Patients who worsened were restarted on IVIg. The primary outcome was total IVIg dose (g/kg) administered from week 16 to 32., Results: There was no difference in total IVIg dose administered after week 16 for patients treated with IFNbeta-1a (1.20 g/kg) compared with placebo (1.34 g/kg; p = 0.75). However, exploratory analyses suggested IFNbeta-1a significantly reduced total dose of IVIg compared with placebo for participants who required either high-dose IVIg (>0.95 g/kg per month) or had greater weakness at baseline (Medical Research Council sum score <51). Adverse events included flu-like symptoms, headache, and fatigue in the IFNbeta-1a groups., Conclusions: Interferon beta-1a (IFNbeta-1a) therapy did not provide significant benefit over IV immunoglobulin (IVIg) therapy alone for patients with chronic inflammatory demyelinating polyradiculoneuropathy. However, IFNbeta-1a might be beneficial for patients with more severe disability or those needing high doses of IVIg., Level of Evidence: This study was designed to provide Class I evidence for the safety and efficacy of IM IFNbeta-1a in the treatment of CIDP but has been subsequently classified as Class II due to a >20% patient dropout rate. Thus, this randomized, controlled clinical trial provides Class II evidence of no effect on primary and secondary endpoints of 4 dosage regimens of IM IFNbeta-1a added to IVIg in persons with CIDP.

A large proportion of demented Lewy body disease patients have Alzheimer's disease (AD)- like pathology, in particular amyloid-beta (Abeta) plaques. Cystatin C (CysC) is a carrier of soluble Abeta (42) in the cerebrospinal fluid (CSF) and reduces Abeta plaque formation. The CST3 BB genotype leads to a reduced secretion of the protein in vitro and increases the risk for AD, suggesting that variability in the CST3 gene and CysC protein concentration may be associated with dementia in Lewy body disease. We therefore determined the CST3 genotype in 51 demented and 71 nondemented Lewy body disease patients, and in 52 controls, as well as CSF CysC and Abeta (42) levels from 132 of these subjects. The CST3 BB genotype was associated with lowered CSF CysC levels and with dementia. Demented Lewy body disease patients had decreased CSF CysC levels. The correlation between CSF CysC and Abeta (42) levels was high in non-demented subjects, but poor in demented patients. We conclude that, in Lewy body disease, the CST3 BB genotype and low CSF CysC levels are associated with dementia, possibly through a disturbed elimination of soluble Abeta(42).

Background: Natalizumab, a humanized monoclonal IgG4 antibody, is an alpha4-integrin antagonist, which inhibits the migration of inflammatory cells into the central nervous system, a key pathogenic mechanism in multiple sclerosis (MS). In a six month, phase II clinical trial of patients with relapsing MS, natalizumab significantly reduced the formation of new gadolinium-enhanced (Gd+) lesions and the number of clinical relapses., Objective: To investigate the relationship of historical relapse rate and new Gd + lesion number with subsequent MS disease activity and natalizumab treatment in the phase II study., Methods: Patients who participated in the phase II study were stratified into subgroups according to: (i) the number of relapses in the two years prior to entry into the study: 2 relapses (n = 108), 3 relapses (n =57), and >3 relapses (n =48); (ii) the number of new Gd + lesions at baseline (Month 0): 0 (n = 129), 1-2 (n =50), and >2 (n =33). Relapses and new Gd + lesions during the treatment phase of the trial were determined and compared for each subgroup., Results: Both the prestudy relapse rate and number of new Gd + lesions at baseline were related to the subsequent risk of a relapse; baseline number of Gd + lesions was related to the likelihood of subsequent new Gd + lesion formation. There was a lower proportion of subjects with an on-study relapse and fewer new Gd + lesions in all natalizumab-treated subgroups when compared with their placebo counterpart; the difference was most apparent in the subgroups of patients with >3 relapses in the two years prior to study entry and >2 new Gd -- lesions at Month 0., Conclusions: There was a lower proportion of subjects with an on-study relapse in natalizumab-treated patients, particularly in those with a more active disease at study entry. Larger ongoing phase III studies will allow more definitive investigation of these preliminary subgroup findings.

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNbeta-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNbeta-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNbeta-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNbeta-1a-Avonex in the phase III trial. Serum levels of IFNbeta antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNbeta-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNbeta-naïve. At baseline, 281 patients were negative for IFNbeta antibodies (NAb-). NAbs (titre > or = 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNbeta-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNbeta-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres < 100; 36 of these 39 seroconverted to NAb- while on IFNbeta-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres > or = 100; five remained NAb+ during six years on IFNbeta-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNbeta-1a-Avonex during the clinical trial were NAb+ with titres < 100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNbeta-1a-Avonex had NAb titres > or = 100; five of these remained NAb+ at six years. No patient with a NAb titre > 1000 seroconverted to NAb-, whether initially treated with IFNbeta-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNbeta-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNbeta product.

Objective: To assess the association of squamous intraepithelial lesions (SIL) on cervicovaginal Papanicolaou (Pap) smear among women infected with HIV-1 and their pregnancy status, and historical and clinical factors., Methods: Study enrollment Pap smears of 452 pregnant and 126 nonpregnant HIV-infected women had cytologic evaluation. The rates of SIL were compared with pregnancy status, immunosuppression, presence of sexually transmitted diseases (STDs) and demographic features., Results: Rates of low grade SIL were similar for pregnant and nonpregnant HIV-1-infected women (17% and 23.8%, respectively; p = .09). Of them, 12 women, 9 pregnant and 3 nonpregnant, had high grade SIL. None had invasive cervical cancer. Low CD4 percentage (odds ratio, [OR] = 3.8; 95% confidence interval [CI], 2.0-7.3) and inflammation (OR = 2.8; 95% CI, 1.8-4.3) were associated with SIL. An association between herpes simplex and SIL (OR = 3.3; 95% CI, 1.1-9.5) was less certain due to clinical diagnosis and low prevalence of herpes simplex (17 of 456 women)., Conclusions: Pap smears for a cohort of HIV-infected pregnant and nonpregnant women revealed a high prevalence of LGSIL but a low prevalence of HGSIL and no cases of cervical cancer. Although pregnancy may not affect the rate of Pap smear abnormalities, SIL is associated with immunosuppression, cervical inflammation, and herpes simplex. Closer surveillance of HIV-1-infected women with these risk factors may be warranted.