Bayer Pharmaceuticals Corporation Research Articles

Fatigue Severity Patterns Differ across Geographical Regions and Ethnic Groups in Patients with Clinically Isolated Syndrome and Early Multiple Sclerosis: First Results from the BEGIN Study (P04.105)

Objective: To evaluate fatigue severity patterns across different regions and ethnic groups in patients with clinically isolated syndrome (CIS) and early relapsing remitting multiple sclerosis (RRMS). Background The Betaferon® treatment and Exercise data Gathering IN early MS (BEGIN) study is a prospective, international, multicentre, observational study over a period of 2 years, assessing self-rated fatigue, depression, health-related quality of life (HRQoL), and physical activity in patients with CIS and early RRMS treated with interferon beta-1b (IFNB-1b). Design/Methods: A total of 770 patients (mean age: 36.2 (SD 9.96); 68.7% female; median time since first clinical event 10.5 months (IQR 17); mean EDSS at baseline: 2.0 (SD 1.91)) were assessed on fatigue by the Fatigue Scale of Motor and Cognitive Functions (FSMC), a recently developed and linguistically validated instrument for MS related fatigue. Ethic groups were distributed as follows: Caucasian: 583, Black: 10; Hispanic: 98; Asian: 43; other: 36. Sub-analyses were performed to evaluate whether fatigue scoring was geographically different. Sample distribution was as follows: Northern Europe (NE) and Northern America (NA): 58; Southern Europe (SE): 231; Eastern Europe (EE): 64; Western Europe (WE): 126; Asia (A): 40; Western Asia (WA): 74; Oceania (O): 74; Latin America (LA): 103. Results: In the total population 32% were classified as having no fatigue, 14% mild, 15% moderate, and 32% severe fatigue. The proportion of patients with severe fatigue was unexpectedly high with regard to the short disease duration. Further analyses revealed highest proportions of fatigue severity (around 40%) in NE and NA, A and O compared to SE, EE, WE, WA and LA. Conclusions: This first exploratory inspection of the data indicates that self-perceived ratings of fatigue differ between regions and ethnic groups. These results are of high relevance when applying patient reported outcomes in multi-centre trials. Supported by: Bayer Pharma AG. Disclosure: Dr. Penner has received personal compensation for activities with Actelion, Bayer-Schering, Biogen Nordic, Merck Serono, Roche, and Teva Aventis.Dr. Penner has received research support from Bayer Schering. Dr. Wicklein has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Beckmann has received personal compensation for activities with Bayer Pharmaceuticals Corporation as an employee. Dr. Daumer has nothing to disclose. Dr. Hagstromer has nothing to disclose. Dr. Sjostrom has nothing to disclose. Dr. Tintore-Subirana has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Merck Serono, Biogen-Idec, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, and Novartis as a consultant and/or speaker.

Cardiac Safety of Fingolimod 0.5 mg during the First Dose Observation in 4-Month, Open-Label, Multi-Center FIRST Study in Patients with Relapsing MS (S41.003)

Objective: To report the safety results of fingolimod 0.5 mg focusing on cardiac events during the first dose observation in relapsing MS patients both without cardiac risk factors and with cardiac conditions not included in fingolimod clinical trials. Background Fingolimod (FTY720) is an S1PR modulator approved for the treatment of relapsing MS. The initiation of fingolimod treatment results in generally asymptomatic and transient bradycardia and may be associated with atrioventricular blocks (AVB). Prescribing information recommends 6 hours on-site observation for signs and symptoms of bradycardia. Design/Methods: 2417 patients were enrolled. Preliminary results are reported for 2289 patients. Unless patients met pre-defined cardiac risk criteria the first dose administration was permitted off-site. Heart rate and ECG abnormalities were assessed by ambulatory Holter-ECG for 24 hours at screening and for 6 hours after administration of the first dose. Results: In the post-dose Holter ECGs the incidence of Mobitz I second degree AVBs was 1.4% and the incidence of 2:1 AVBs was 0.5%. One patient had a finding of >3 sec pause in both screening and post dose Holter-ECG. Incidence of conduction abnormalities was similar in patients monitored on-site (n=1162) and off-site (n=1127) and in patients with or without cardiac risks. One patient discontinued study drug due to the second degree AVB. No patient had a HR Conclusions: Overall incidence of AVBs on Holter-ECGs was low, irrespective of on- or off-site first dose administration or the presence of potential cardiac risk factors. These results are similar to those observed in fingolimod trials and confirm the benign nature of the cardiac effects of treatment initiation with fingolimod. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Palace has received personal compensation for activities with Teva Neuroscience, Biogen Idec, Merck Serono, and Bayer Schering Pharma. Dr. Palace has received research support from GlaxoSmithKline, Inc. Dr. Gottschalk has received personal compensation for activities with Novartis as an employee. Dr. Bijarnia has received personal compensation for activities with Novartis Healthcare Pvt Ltd as an employee. Dr. Keil has received personal compensation for activities with Novartis as an employee. Dr. Tomic has received personal compensation for activities with Novartis as an employee. Dr. von Rosenstiel has received personal compensation for activities with Novartis Pharma AG. Dr. von Rosenstiel holds stock and/or stock options in Novartis Pharma AG, which sponsored research in which Dr. von Rosenstiel was involved as an investigator. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience.

Immune Tolerance Induction with High-Dose Intravenous Interferon-beta in Multiple Sclerosis Patients with Neutralizing Antibodies - A Pilot Study (P04.121)

Objective: To investigate if high-dose intravenous interferon-beta (IFNb) in high-titer neutralizing antibody-(NAb)-positive multiple sclerosis (MS) patients reduces NAb titers to less than 100 neutralizing units (NU) - presumably by induction of immune tolerance (IT) - and restores IFNb bioavailability measured by myxovirus protein A (MxA) concentrations. Background IFNb is associated with the generation of NAbs affecting treatment efficacy. Successful IT induction has been shown for hemophilia patients with NAbs against recombinant factor-VIII by high-dose intravenous administration of factor-VIII. Design/Methods: 9 MS patients, with a NAb titer of >=500 NU, received 48 MIU IFNb-1b intravenously once weekly over 3 months. Blood samples were collected at screening, monthly before and 4 hours after infusions, and at follow-up after 6 months for NAb and MxA measurement. Disease activity was monitored by brain MRI and EDSS assessments. Results: Median NAb titer at baseline was 1429 NU. Titers determined before each infusion did not change over the treatment period. There was a significant decrease of titers four hours after each infusion. NAb titers at follow-up did not significantly differ compared to titers at screening. Comparing NAb titers after 3 months to baseline, 4 patients showed increased titers by 654 NU and 5 decreased titers by 235 NU indicating a possible responder group. MxA levels were significantly elevated after all IFNb infusions reaching a median value of 206. MRI data are currently being analyzed. Conclusions: Weekly intravenous IFNb induced short-term bioactivity in patients with high NAb titers but failed to induce long-term reversion of NAb although in some patients a trend towards reversion was observed. Supported by: Bayer Schering Pharma. Disclosure: Dr. Hegen has received personal compensation for activities with Bayer PHarmaceuticals Corporation, Schering-Plough Corporation, Biogen Idec, Merck Serono as speaker. Dr. Guger has nothing to disclose. Dr. Harrer has nothing to disclose. Dr. Hoelzl has nothing to disclose. Dr. Kraus has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck-Serono, Novartis, Genzyme Corporation as a consultant. Dr. Kraus has received research support from Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck Serono, Novartis, Genzyme Corporation. Dr. Skrobal has nothing to disclose. Dr. Schautzer has nothing to disclose. Dr. Schmidegg has nothing to disclose. Dr. Deisenhammer has received personal compensation for activities with Biogen Idec, Merck Serono, Bayer and Sanofi. Dr. Deisenhammer has received research support from Bayer HealthCare.

Glatiramer Acetate Complements Anti-CD20-Mediated B-Cell Depletion in Treatment of CNS Autoimmune Disease (P04.124)

Objective: To investigate whether glatiramer acetate (GA) may complement immunomodulatory properties of anti-CD20 in the multiple sclerosis (MS) model experimental autoimmune encephalomyelitis (EAE). Background Recent MS trials demonstrated that therapeutic B-cell depletion reduces formation of central nervous system inflammatory lesions, which may relate to an impaired activation of encephalitogenic T-cells. Experimental evidence indicates however that B-cell depletion is also associated with an enhanced pro-inflammatory differentiation of myeloid APC, indicating that anti-CD20 collaterally depletes subset(s) of B-cells with regulatory properties. We hypothesized that GA treatment, which immunomodulates myeloid APC, may reverse loss of B-cell APC regulation and complement anti-CD20 in treatment of CNS autoimmune disease. Design/Methods: We tested the combination of anti-CD20 and GA in two models; in MOG protein-induced EAE, in which activated B-cells contribute to disease development and in MOG p35-55-induced EAE, a model which does not involve B-cells. Female C57Bl/6 mice were injected weekly with 0.2mg of murine anti-CD20 or isotype starting 3 weeks prior to immunization. Upon EAE onset, mice were randomized to receive 150µg GA/d or PBS alone; representative mice were evaluated for cytokine production (TNF, IL-10) of CD11b + APC. Results: In EAE induced by MOG p35-55, anti-CD20 exacerbated disease severity, which was associated with a pronounced pro-inflammatory cytokine profile of myeloid APC (more TNF, less IL-10). Additive GA treatment reversed EAE exacerbation and restored APC cytokine production to the levels of non-B-cell-depleted mice. In MOG protein-induced EAE, anti-CD20 treatment abrogated development of myelin-specific T-cells and ameliorated disease severity despite a similar pro-inflammatory differentiation of myeloid APC. GA treatment again reversed pro-inflammatory APC differentiation, which, in this model, was associated with synergistic clinical benefit of GA and anti-CD20. Conclusions: Collectively, our findings suggest that GA-treatment counterbalances concomitant loss of B-cell regulation upon pan-B-cell depletion. Additive GA-treatment may be useful to enhance both safety and effectiveness of anti-CD20 in treatment of MS. Disclosure: Dr. Hertzenberg has nothing to disclose. Dr. Lehmann-Horn has nothing to disclose. Dr. LaLive has nothing to disclose. Dr. Bernard has nothing to disclose. Dr. Zamvil has received personal compensation for activities with Biogen Idec, Teva Neuroscience and EMD Serono-Pfizer. Dr. Zamvil has received research support from the National Institutes of Health, National Multiple Sclerosis Society, the Maisin Foundation, the Guthy Jackson Charitable Foundation, Teva Neuroscience, and Boehringer Ingelheim Pharmaceuticals, Inc. Dr. Hemmer has received personal compensation for activities with Hoffmann la Roche, Merck Serono, Biogen Idec, Novartis, Micromet and Bayer Pharmaceuticals Corporation as scientific advisor and speaker. Dr. Hemmer has received research support from Novartis, Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono and Teva Neuroscience. Dr. Weber has received personal compensation for activities with Hoffmann-LaRoche, Genentech, Inc., Novartis, Bayer Pharmaceuticals Corporation, Merck Serono, Biogen Idec and Teva Neuroscience as a speaker and/or participant on an advisory board. Dr. Weber has received research support from Teva Neuroscience.

Long-Term Efficacy and Safety of Fingolimod (FTY720) in Relapsing-Remitting Multiple Sclerosis (RRMS): Results from the Extension of the Phase III FREEDOMS Study (S41.004)

Objective: To report long-term efficacy and safety of fingolimod in RRMS, from the phase III FREEDOMS study extension. Background RRMS patients randomized to oral, once-daily(o.d), fingolimod (0.5mg or 1.25mg) in the 2-year, double-blind, FREEDOMS core study, demonstrated a significant improvement in clinical and MRI endpoints versus placebo (PBO)-treated patients. We present here end of study (EOS) results from the extension phase of upto 4 years treatment. Design/Methods: In the extension, patients either continued on the core phase dose (continuous-fingolimod), or were re-randomized (1:1) from placebo to fingolimod (1.25 or 0.5mg/o.d) (PBO-fingolimod). All patients received open-label 0.5mg following a decision to discontinue the fingolimod 1.25mg/day treatment arm from all MS studies. Results: 1033/1272 (81.2%) patients enrolled in FREEDOMS completed the 24M core, and 773/920 (84%) patients enrolled in the extension (60.7% of initially randomized) completed the study. Common reasons for discontinuations were withdrawal of consent (7.2%) and adverse events (AE) (3.4%). Annualized relapse rates (ARR) decreased in the switch/PBO-fingolimod group during the extension phase (PBO-1.25mg, 0.22; PBO- 0.5mg, 0.19) versus the core (ARR= 0.4; p Conclusions: Patients who switched from placebo to fingolimod showed significant improvements in clinical and MRI outcomes (including brain atrophy). Continuous fingolimod treatment was associated with sustained low clinical and MRI disease activity and was well-tolerated. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Radue has received personal compensation for activities with AIM, Biogen Idec, and Novartis as a consultant.Dr. Radue has received research support from Actelion, Bayer Schering, Biogen Idec, Merck Serono, and Novartis. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. Polman has received personal compensation for activities with Biogen Idec, Schering AG, Teva Neuroscience, EMD Serono, Novartis, GlaxoSmithKline, Inc., UCB Pharma, AstraZeneca Pharmaceuticals, Roche Diagnostics and Antisense Therapeutics as a consultant or speaker.Dr. Polman has received research support from Biogen Idec, Schering AG, GlaxoSmithKline, Inc., Novartis, EMD Serono and Teva Neuroscience. Dr. Hohlfeld has received personal compensation for activities with Schering AG, Merck-Serono, Biogen Idec, Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc.,Novartis, Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Hohlfeld has received personal compensation in an editorial capacity for International MS Journal.Dr. Hohlfeld has received research support from Schering AG, Merck-Serono, Biogen Idec, Teva Neuroscience, Norvartis. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex. Dr. Calabresi has received research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Agoropoulou has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Jin has received personal compensation for activities with Novartis Pharma AG. Dr. Zhang-Auberson has received personal compensation for activities with Novartis as an employee. Dr. Francis has received personal compensation for activities with Novartis as an employee. Dr. Francis holds stock and/or stock options in Novartis, which sponsored research in which Dr. Francis was involved as an investigator.

The Effect of Fingolimod on Peripheral Blood Mononuclear Cell Phenotypes: A Prospective Study (P02.122)

Objective: To report changes in peripheral blood lymphocyte subpopulations in patients with relapsing-remitting multiple sclerosis (RRMS) treated with fingolimod prospectively over 6 months and to explore potential surrogate markers that may be associated with a clinical response to treatment. Background Fingolimod is a recently approved drug for treating RRMS inhibiting the sphingosine-1-phosphate-dependent lymphocyte egress from secondary lymphoid tissues resulting in reversible lymphopenia. Specific immunological changes in the peripheral venous blood have only been explored cursory in small patient numbers. Design/Methods: This is a prospective, multi-center, single-arm, open-label study in 445 RRMS patients receiving 0.5 mg fingolimod. At predefined time points (baseline, 1 month, 4 months, as well as 6 months after treatment initiation) blood samples were obtained. Leukocytes were analyzed by flow cytometry for the expression of various surface markers (CD3, CD4, CD8, CD16, CD19, CD34, CD45RA, CD56, CCR7), whereas serum samples were analyzed for the presence of various cytokines, such as for Th1, Th2 and Th17 responses. Results: The analysis of the first 100 patients revealed that the number of CD45 positive cells decreased and maintained at low levels for the follow-up. Numbers of CD4+, CD8+, and CD19+ cells were lowered. The change in the CD4+/CD8+ ratio was determined by an intended reduction of CD4+ T cells and a slight reduction of CD8+ T cells. CD4+ cells however, were never found to be depleted. For the majority of the cytokines tested so far, no significant alterations were found. The study is still ongoing and data for the majority of the patients will be available. Conclusions: Fingolimod induces a robust effect predominantly on CD4+ T cells, an effect maintained over time. Biomarkers predicting clinical efficacy and/or safety signals have not been identified yet and require further prospective studies. Supported by: Novartis Pharma GmbH, Nuernberg, Germany. Disclosure: Dr. Dehmel has nothing to disclose. Dr. Opgenoorth has nothing to disclose. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Diaz-Lorente has received personal compensation for activities with Novartis Pharmaceuticals as an employee. Dr. Kieseier has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis, Roche Diagnostics, Sanofi-Aventis Pharmaceuticals, and TEVA Neurosciences as speaker. Dr. Kieseier has received research support from Bayer Pharmaceuticals, Biogen Idec, Merck Serono and Teva Neurosciences.

Clinical Efficacy of Laquinimod for the Treatment of Multiple Sclerosis; Pooled Analyses from the ALLEGRO and BRAVO Phase III Trials (S01.007)

Clinical Efficacy of Laquinimod for the Treatment of Multiple Sclerosis; Pooled Analyses from the ALLEGRO and BRAVO Phase III Trials (S01.007)

Is Systemic Thrombolysis Justified in Patients with Ischemic Stroke and Recent Dental Extraction? (P03.009)

Objective: To report the management of accidental oral bleeding due to unreported dental extraction following systemic thrombolysis for acute ischemic stroke. Background The rate of patients with acute ischemic stroke in close temporal relationship with surgical interventions is steadily increasing. We here report on the management of accidental hemorrhagic complications following unreported surgery within the oral cavity. Design/Methods: CASE 1: A 69-year-old woman was admitted with acute onset of severe right-sided hemiparesis, neglect and global aphasia one hour earlier (NIHSS 19). Systemic thrombolysis was started and bleeding from the oral cavity was observed after 35 mg rt-PA. Local compressive therapy and fibrin glue applied by a maxillofacial surgeon could effectively halt the bleeding. The subsequent endovascular recanalisation procedure was unremarkable. CASE 2: A 86-year-old woman developed acute left-sided hemiparesis, dysarthria and facial palsy (NIHSS 20). A total of 80 mg rt-PA was given i.v and was followed by endovascular recanalisation. During the procedure, however, severe pulsatile bleeding from the oral cavity was observed. Local compressive therapy and suturing by an otorhinolaryngologist was able to stop the bleeding. Results: Whereas both patients had undergone recent minor surgical procedures within the oral cavity, these were not disclosed during the assessment of the medical history. Bleeding occurred early and could be stopped by prompt discontinuation of rt-PA and compressive therapy. Recanalization was achieved by endovascular intervention in both cases. Conclusions: In the work-up of acute ischemic stroke, inspection of the oral cavity and explicit inquiry on recent dental extraction should be performed. While the management of the bleeding within the oral cavity was successful in our cases, further studies are required to stratify the risk of thrombolysis in patients with minor surgery when local compressive therapy but not mechanical recanalisation is available. Disclosure: Dr. Seifert has nothing to disclose. Dr. Sprenger has received personal compensation for activities with Allergan, Eli Lilly, Biogen Idec, and Bayer. Dr. Mucke has nothing to disclose. Dr. Forschler has nothing to disclose. Dr. Poppert received personal compensation in an editorial capacity for Bayer and EV3.Dr. Poppert received research support from Takeda, DFG and Wirtschaft and Technologie. Dr. Hemmer has received personal compensation for activities with Hoffmann la Roche, Merck Serono, Biogen Idec, Novartis, Micromet and Bayer Pharmaceuticals Corporation as scientific advisor and speaker. Dr. Hemmer has received research support from Novartis, Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono and Teva Neuroscience. Dr. Sellner has received personal compensation for activities with Novartis, Merck-Serono, and Sanofi-Aventis.

The CombiRx Trial: A Multi-Center, Double-Blind, Randomized Study Comparing the Combined Use of Interferon Beta-1a and Glatiramer Acetate to Either Agent Alone in Participants with Relapsing-Remitting Multiple Sclerosis - Clinical Outcomes (PL02.003)

Objective: To determine if combined use of interferon beta-1a (IFN) 30ug weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either alone in relapsing remitting multiple sclerosis (RRMS). Background This double-blind, multi-center, randomized RRMS clinical trial compared IFN plus GA versus single agent arms with matching placebo. Entry criteria included: EDSS ≤ 5.5, RRMS, age 18-60, ≥2 relapses in prior 3 years and no prior use of either medication. Design/Methods: 1,008 participants were randomized and underwent quarterly clinical assessments until the last subject enrolled completes 3 years in January 2012. Magnetic resonance imaging (MRI) was done at baseline and 6, 12, 24 and 36 months. The primary MRI variable was change in the Z4 composite MRI score (unweighted sum of the individual Z scores for enhanced tissue, T2-hyperintense and T1-hypointense lesion volumes, and normalized CSF - an inverse measure of atrophy) from baseline to 36 months by treatment cohort using general linear models. Assuming differences between groups on the Z4 composite, selected additional measures will be formally addressed as follows: cumulative sum of the number of enhanced and unique active lesions, differences in the cubed root of the T2 and T1 lesion volumes, and differences in brain atrophy analyzed over the 36 months on intent to treat basis. Results: Recruitment occurred from January 2005-April 2009. At baseline 39.7% of participants had enhancements, a median total T2 lesion volume of 7.48 ml (T1-hypointense component 0.84 ml), and mean Z4 composite = 0. On study MRI data will be provided, with clinical outcome data presented separately. Conclusions: CombiRx was a uniquely sponsored collaboration between NIH, academic institutions, practicing neurologists and pharma/biotech; the largest test thus far of the potential for combining immunotherapies in early RRMS. It provides the longest controlled clinical, MRI and biomarker dataset of any MS trial. Supported by: NIH/NINDS (5U01NS045719). Disclosure: Dr. Wolinsky has received personal compensation for activities with Astellas, Bayer Pharmaceuticals Corporation, Bayer Multiple Sclerosis Council, Celgene Corporation, Eli Lilly & Company, Roche Diagnostics Corporation, Novartis, Sanofi-Aventis Pharmaceuticals and Teva Neuroscience as consultant and participant on monitoring and advisory boards. Dr. Wolinsky has received (royalty or license fee or contractual rights) payments from University of Texas Health Science Center at Houston. Dr. Wolinsky has received research support from Sanofi-Aventis Pharmaceuticals, Inc. Dr. Narayana has received personal compensation for activities with Teva Neuroscience. Dr. Nelson has received personal compensation for activities with Bayer HealthCare, Biogen Idec, EMD Serono, National MS Society, MS Association of America, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, and the University of Massachusetts Medical School. Dr. Nelson has received research support from Novartis and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Datta has nothing to disclose. Dr. Cofield has received personal compensation for activities with GlaxoSmithKline, Inc., Teva Neuroscience, Orthotech Biotech, the Department of Defense, and the American Academy for Orthopedic Surgery. Dr. Cutter has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Cleveland Clinic, Daiichi Pharmaceutical Corporation, GlaxoSmithKline, Inc., Genmab Biopharmaceuticals, Eli Lilly & Company, Medivation, Modigenetech, Ono Pharmaceutical, PTC Therapeutics, Teva Neuroscience, Vivus, University of Pennsylvania, NHLBI, NINDS, NMSS, Alexion, Bayhill Therapeutics, Bayer Pharmaceuticals Corporation, Celgene, Novartis, Consortium of MS Centers, Genzyme Corporation, Klein-Buendel Incorporated, Nuron Biotech, Peptimmune, Somnus Pharmaceuticals, Sandoz, University of Texas Southwestern and Visioneering Technologies, Inc. Dr. Cutter has received compensation for serving on the board of Pythagoras, INC. Dr. Cutter has received research support from various pharmaceutical corporations. Dr. Conwit has nothing to disclose. Dr. Gustafson has nothing to disclose. Dr. Lublin has received personal compensation for activities with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, and MedImmune as a consultant.Dr. Lublin has received personal compensation in an editorial capacity for Elsevier: Multiple Sclerosis and Related Diseases. Dr. Lublin has received personal compensation for activities with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Pfizer, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, MorphoSys, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, and MedImmune as a consultant.Dr. Lublin has received personal compensation in an editorial capacity for Elsevier: Multiple Sclerosis and Related Diseases.

TLR2 Mediated CD39+Treg Induction by a Human Gut Commensal Antigen Protects EAE Mice and Restores Impaired Treg Function in Man (P05.107)

Objective: To assess the role for gut commensal bacteria in CNS demyelination. Background Our understanding for the role of the gut microbiota in the control of autpimmunity is evolving. We have identified a polysaccharide (PSA) produced by the human commensal B.fragilis that confers protection to EAE in mice. Gut associated CD103+ dendritic cells (DCs) accumulate within the CLN of PSA immunized EAE mice. These CD103+ DCs enhance the conversion of naive CD4+ T cells into protective IL-10-producing FoxP3+ T cells. The role of gut commensal microbiota in human MS has yet to be established. Design/Methods: CD103+/- DCs were co-cultured with CLN isolated CD4+ T cells in the presence of purified PSA (100 μg/ml). FoxP3+CD39+ and IL-10 production by CD4+T cells was determined by FACS and ELISA. Fluorochrome labeled PSA was used to identify the DC subpopulations from the PBMC that was associated with PSA uptake. PBMC were isolated from those with defined RRMS naive or off treatment x 30 days. Results: TLR2 deficiency impaired uptake of PSA. CD103+DCs from intact mice but not TLR2-/- provoked the acquisition of sFoxP3+ phenotype. PBMCs from TLR2 deficient mice were unable to convert CD4+ T cells into FoxP3+Tregs. TLR2 was critical for the IL-10 production as well as the upregulation of CD39+ Tregs in both humans with MS and EAE mice. The protection induced by oral immunization with PSA was abrogated in TLR2 mice confirming the essential role of TLR2 protection elicited PSA. Conclusions: TLR2 signaling is essential in the experimental protection by the human B. fragilis antigen PSA. This antigen can induce IL-10+ secreting CD39+ Tregs in both humans with MS and mice with EAE. The induction of this regulatory phenotype and cytokine profile by PSA could potentially act as therapeutic for the restoration of the Treg impaired function in those with MS. Supported by: NMSS Center of Collaboration and the Murray Bornstein Fellowship. Disclosure: Dr. Kasper has received personal compensation for activities with Teva Neuroscience, Serono, Inc., Bayer Pharmaceuticals Corporation, Genentech, Inc., Mederex as a consultant and participant on a scientifc advisory board. Dr. Kasper has received research support from Teva Neuroscience, Serono, Inc. and Bayer Pharmaceutical Corporation. Dr. Ochoa-Reparaz has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Telesford has nothing to disclose. Dr. Begum-Haque has received research support from Teva Neuroscience. Dr. Mielcarz has nothing to disclose.

IFNbeta-1b Treatment Alters the Composition of Circulating B Cell Subsets, in Particular Reducing the Number of Autoantibody Secreting B1 Cells in Patients with Relapsing-Remitting Multiple Sclerosis (P02.086)

Objective: The hypothesis tested is that B cell subsets in RRMS patients differ from healthy controls and that treatment with IFN-1b alters these subsets. Background Therapy directed at the depletion of CD20+ B cells has been shown in Phase II clinical trials to be effective in reducing relapse rate and improving MRI in those with RRMS. A subset of human autoantibody producing cells, B1 cells, has recently been described. B1 cells present antigen efficiently and induce naive CD4 T cells to become Th17 cells, a major pro-inflammatory compartment that is involved in the pathogenesis of human RRMS. These cells are found in low frequency in peripheral blood and are CD20+CD27+CD43+. This study investigates the phenotype of B cells from patients pre- and post-treatment with IFNbeta-1b. Design/Methods: Blood was drawn from 10 healthy donors and from 10 RRMS patients before treatment and again 2 and 6 months after daily injections of IFNbeta-1b. Cryopreserved PBMCs were thawed and stained with panels of antibodies against B cell surface antigens. Results: At baseline, RRMS patients have increased frequencies of CD19+CD20+ B cells and decreased frequencies of memory B cells. Notably, those with RMS have a 2-to-3-fold higher frequency of B1 cells compared to healthy controls at baseline. B1 cells from RRMS patients express more CD5 when compared with healthy controls. In response to treatment with IFNbeta-1b, the number of circulating B1 cells declines. Conclusions: This study demonstrates an increased frequency in the number of circulating B cells that carry a phenotype consistent with autoantibody-producing B1 cells in those with RRMS. This population of cells is reduced in response to treatment with IFNbeta-1b. Although the number of subjects in this study was limited, these findings suggest that this B1 population may be linked to an increase in disease activity. Supported by: Bayer HealthCare Pharmaceuticals Inc. Disclosure: Dr. Mielcarz has nothing to disclose. Dr. Bergeron has nothing to disclose. Dr. DeLong has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Heyn has nothing to disclose. Dr. Mack has nothing to disclose. Dr. Conrad has nothing to disclose. Dr. Oliver has nothing to disclose. Dr. Kasper has received personal compensation for activities with Teva Neuroscience, Serono, Inc., Bayer Pharmaceuticals Corporation, Genentech, Inc., Mederex as a consultant and participant on a scientifc advisory board. Dr. Kasper has received research support from Teva Neuroscience, Serono, Inc. and Bayer Pharmaceutical Corporation. Dr. Channon has nothing to disclose.

Regulatory T Cells Determine Disease Severity in Experimental Autoimmune Neuropathies (IN1-1.006)

Objective: Inflammatory neuropathies are human autoimmune disorders with considerable disease variability. We here analyzed whether regulatory T cells (Tregs) determine disease severity and manifestation in murine models of autoimmune neuropathies. Background Tregs are potent suppressors of autoimmunity and a reduced Tregs frequency or dysfunction has been associated with different human autoimmune disorders. Inflammatory neuropathies, such as the Guillain-Barre syndrome, are disabling human disorders that feature significant disease variability. It remains unknown if Tregs explain this variability. Design/Methods: We used anti-CD25 antibodies to deplete Tregs in mice with actively induced experimental autoimmune neuritis (EAN) and adoptively transferred chronic neuritis from intercellular adhesion molecule-1 deficient non-obese diabetic mice and analyzed clinical, electrophysiological and histological measures of disease severity. Results: Treg numbers were successfully reduced by antibody administration. Early Treg depletion increased clinical EAN severity and histological signs of peripheral nerve inflammation in EAN and adoptively transferred chronic neuritis. Myelin specific T cell proliferation was increased by Treg depletion. Late stage Treg depletion after initial disease manifestation did not exacerbate inflammatory neuropathy models further. Conclusions: We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but not after the disease has manifested. Disclosure: Dr. Meyer Zur Hoerste has received personal compensation for activities with Bayer Schering and Merck Serono. Dr. Meyer Zur Hoerste has received personal compensation in an editorial capacity from Remedica Education and Publishing. Dr. Meyer Zur Hoerste has received research support from the Firtz-Thyssen Foundation and the Peripheral Nerve Society. Dr. Cordes has nothing to disclose. Dr. Mausberg has received personal compensation for activities with Merck Serono. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant. Dr. Kieseier has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis, Roche Diagnostics, Sanofi-Aventis Pharmaceuticals, and TEVA Neurosciences as speaker. Dr. Kieseier has received research support from Bayer Pharmaceuticals, Biogen Idec, Merck Serono and Teva Neurosciences.

Astrocytes Secrete Bridging Molecules That May Be Responsible for Increased Microglial Uptake of Apoptotic Inflammatory Cells (P07.090)

Objective: To investigate whether astrocyte-conditioned medium (ACM) increases microglial phagocytosis of apoptotic inflammatory cells and which factors mediate this effect. Background The removal of apoptotic T-cells in situ is crucial for the clinical recovery of T-cell mediated neuro-inflammatory diseases. Efficient phagocytic removal prevents secondary immune responses and a leakage of potentially harmful contents of dying cells. Microglia (MG) are the resident scavenger cells in the CNS and play an important role in the clearance of apoptotic cells. Design/Methods: Microglia and astrocytes with >95% purity from newborn Lewis rats were isolated. ACM was collected from astrocyte monolayers after 24 hrs. Effects of ACM on microglial phagocytosis of apoptotic thymocytes were investigated in a light-microscopic based in vitro phagocytosis assay. ACM was further analyzed using both 2D gel-electrophoresis in combination with mass spectrometry and additionally a label-free bottom up approach based on liquid chromatographic separation of peptides and subsequent mass spectrometric identification and quantification. Results: ACM increases microglial phagocytosis specifically for apoptotic cells by 38%(p Conclusions: Astrocytes may be involved in the resolution of autoimmune inflammation attack through secretion of phagocytosis promoting factors such as Annexin A1, Gas-6, and Protein S, which activate MG and/or bridge apoptotic cells to phagocytes. The release of these factors could be crucial for the removal of apoptotic T-cells, thereby maintaining tissue homeostasis and promoting tissue repair. Disclosure: Dr. Minwegen has nothing to disclose. Dr. Poschmann has nothing to disclose. Dr. Stuehler has nothing to disclose. Dr. Faissner has nothing to disclose. Dr. Haghikia has nothing to disclose. Dr. Meyer has nothing to disclose. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Chan has received personal compensation for activities with Bayer Schering, Biogen Idec, Merck Serono, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Chan has received research support from German Ministry for Education and Research, Bayer Schering, Biogen Idec, Merck Serono and Novartis.

The Regulatory Function of B Cells in Protection Against EAE by a Human Commensal Bacteria Polysaccharide (P05.111)

Objective: To investigate the regulatory role of B cells in intestinal commensal Bacteroides fragilis polysaccharide A (PSA) protection of EAE. Background Intestinal commensal microbiota have the potential to modulate immune system against neuro-inflammation. Polysaccharide A (PSA), a zwitterionic capsular polysaccharide derived from the intestinal commensal Bacteroides fragilis and TLR2 agonist, is shown to protect mice against EAE via oral administration route. In this study, we will investigate the the regulatory function of B cells is one of the potential mechanisms underlying PSA protection against EAE. Design/Methods: CD19 + B cells from PSA or BPS orally administrated B6 donor mice were adoptively transferred to EAE-induced B6 recipient mice. Normal or TLR2 -/- CD19 + B cells were in vitro cultured with PSA for 72 hrs and supernatant IL-10 was measured by ELISA. IL-10-Thy1.1 (10BiT) reporter mice was induced with EAE and oral administrated of PSA or PBS as control. Cervical, mesenteric LNs and peyer9s patches were collected. Total CD19 + B cells and CD29 + CD19 + B cells were analyzed for their composition and IL-10 expression by FACS. Results: CD19 + B cells from PSA sensitized donors had stronger protective power against EAE than normal donors in a dosage-dependent manner. In vitro , PSA could stimulate CD19 + B cells production of IL-10 via TLR2 signaling. In vivo at early EAE development stage, PSA can tilt the composition of CD19 + B cells to CD5 + B1 phenotype and IL-10 expressive. Within the CD29 + CD19 + B cell niche, IL-10 + CD5 + B 1 cells are enriched. Conclusions: In MS/EAE, PSA tunes the CNS immuno-homeostasis via B cells. PSA could increase the IL-10 producing B1 subset. PSA enriches IL-10 + regulatory B cell type within brain homing niche, consistent with the reduction of neuro-inflammation by PSA treatment. TLR2 sensing of PSA both in vivo and in vitro is essential for the establishment of anti-inflammation function via PSA. Supported by: NIAID-AI061939 and CA1027A1/3-National Multiple Sclerosis Society. Disclosure: Dr. Wang has nothing to disclose. Dr. Telesford has nothing to disclose. Dr. Ochoa-Reparaz has nothing to disclose. Dr. Haque-Begum has received research support from Teva Neuroscience. Dr. Mielcarz has nothing to disclose. Dr. Kasper has nothing to disclose. Dr. Kasper has received personal compensation for activities with Teva Neuroscience, Serono, Inc., Bayer Pharmaceuticals Corporation, Genentech, Inc., Mederex as a consultant and participant on a scientifc advisory board. Dr. Kasper has received research support from Teva Neuroscience, Serono, Inc. and Bayer Pharmaceutical Corporation.

Treatment of Neurological Autoimmune Disorders with Rituximab - A 7 Years Single Center Experience (P04.140)

Objective: To characterize patients with neurological autoimmune disorders (NADs) who have been treated with the therapeutic monoclonal antibody rituximab in our center. Background Rituximab depletes peripheral CD20-bearing B cells. Clinical efficacy in relapsing-remitting multiple sclerosis (MS) was shown in a phase II trial. Treatment benefits for neuromyelitis optica (NMO), inflammatory neuropathies (IN) and myasthenia gravis (MG) can be deduced from published open label case series. Design/Methods: Databases of patient records and pharmacy prescriptions at Heinrich-Heine university medical center were queried to identify patients with NADs who received at least one treatment with rituximab. Patient records were reviewed for epidemiological and disease related parameters. Results: Since 2004 61 patients (mean age 46 ±16 years; 67 % females) have been treated with a median of 1600 mg of rituximab applied in a median of 3 cycles. A total of 258 cycles were administered, resulting in 146 patient-years of follow-up. The majority of patients (n=35) had a diagnosis of MS, 6 patients suffered from NMO-spectrum disorders, 3 patients from MG, 13 from IN, and 4 cases suffered from other NADs. Rituximab treatment was initiated after a median interval of 11 years (range 1 month – 30 years) of making the respective diagnosis. Prior to rituximab patients had received a median of 6 (range 0-7) different immunomodulatory and/or –suppressive medications. In 76 % of patients rituximab was considered initially effective as judged by the treating physicians based on clinical and/or paraclinical parameters. Efficacy was least noted in patients with IN (50 %) and progressive MS without relapses (62 %). Adverse events occurred in 20 % of patients, most frequently in patients with IN (31 %). Conclusions: This open-label retrospective case series study provides evidence that rituximab treatment may be effective in selected patients with NADs even if initiated late in the disease course or if standard therapies have failed. Disclosure: Dr. Menge has received personal compensation for activities with Biogen Idec, Bayer HealthCare and Serono as a speaker. Dr. Meyer Zur Hoerste has received personal compensation for activities with Bayer Schering and Merck Serono. Dr. Meyer Zur Hoerste has received personal compensation in an editorial capacity from Remedica Education and Publishing. Dr. Meyer Zur Hoerste has received research support from the Firtz-Thyssen Foundation and the Peripheral Nerve Society. Dr. Jander has nothing to disclose. Dr. Ringelstein has nothing to disclose. Dr. Aktas has received personal compensation for activities with the German Research Council (DFG SFB-TRR43) and Bayer HealthCare, BiogenIdec, Merck-Sorono, Novartis, and Teva/Sanofi-Aventis. Dr. Kieseier has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis, Roche Diagnostics, Sanofi-Aventis Pharmaceuticals, and TEVA Neurosciences as speaker. Dr. Kieseier has received research support from Bayer Pharmaceuticals, Biogen Idec, Merck Serono and Teva Neurosciences. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant.

Glatiramer Acetate Mediated Expression of 4 1integrin (VLA-4) on T and B Regulatory Cells in EAE Mice (P02.109)

Objective: To evaluate the effect of glatiramer acetate (GA) on the induction of α4β1 (VLA-4) on regulatory T/B cells in EAE mice. Background α4β1 expressing B cells and CD4+ T cells are important in the effector phase of EAE. Regulatory cells (CD4+CD25+ or CD19+CD5+) impact disease progression in EAE and perhaps human MS. Both B and Treg cells protect against disease by the secretion of specific anti-inflammatory cytokines including IL-10 as well as important trafficking molecules. Design/Methods: An immunosuppression assay was performed using GA sensitized lymphocytes at varying ratios in the presence of mAb to a4. Cellular isolates were obtained from GA treated EAE mice and phenotyped for T/B regulatory cell expression by FACS and mRNA secretory expression for various chemokines (CXCR4, 5, MIP1 alpha) cytokines and neurotrophic factors including BDNF. Results: Higher expression of both T and B regulatory phenotypes were observed in GA treated mice. Lymphocyte suppression (50% at 1:1 ratio) by regulatory cells was unaffected by exposure to anti-α4. Increased IL-10 and decreased IFNγ was measured in T and B cells from GA treated mice. No significant difference in α4β1 expression was observed on regulatory T or B cell obtained from GA immunized mice compared to control mice. An increase in MZ B cells (B220+CD21hiCD23lo) was observed in GA treated mice. Further studies are underway that will focus on the identification of these cells within the CNS. Conclusions: GA may influence the conditioning of the Treg/Breg response that appears independent of α4β1 expression. The increased number of T/B regulatory cells represents an important mechanism in the suppression of EAE pathogenesis. GA conditioned B cells have a significant down regulatory effect on chemokines CXCR4, CXCR5 and TLR9 expression in spleen and within the CNS that may be responsible for mediating anti-inflammatory effects in EAE induced mice. Supported by: Teva Neuroscience and NIAID-AI061938, and CA1027A1/3 - National Multiple Sclerosis Society. Disclosure: Dr. Begum-Haque has received research support from Teva Neuroscience. Dr. Christy has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Telesford has nothing to disclose. Dr. Haque has nothing to disclose. Dr. Kasper has received personal compensation for activities with Teva Neuroscience, Serono, Inc., Bayer Pharmaceuticals Corporation, Genentech, Inc., Mederex as a consultant and participant on a scientifc advisory board. Dr. Kasper has received research support from Teva Neuroscience, Serono, Inc. and Bayer Pharmaceutical Corporation.

Natalizumab and Pregnancy - Results from the German MS and Pregnancy Registry (P06.187)

Objective: To present safety data of natalizumab exposure during pregnancy. Secondly, to assess the natalizumab serum concentration in the newborns to evaluate the transplacentar transport of natatlizumab. Thirdly, to assess relapses during pregnancy in exposed women who stopped the treatment after becoming aware of pregnancy. Background Natalizumab is recommended to be withdrawn 3 months prior to pregnancy. Few data are available about exposure during pregnancy. Reports of rebound of disease activity have been published, if patients stopped natalizumab. Design/Methods: We enrolled pregnant women with MS nationwide being exposed at some timepoint of pregnancy to natalizumab. Results: We identified 74 pregnancies with natalizumab exposure during pregnancy; most of them stopped treatment in the first trimester. 11 of these pregnancies (14,8%) resulted in early spontaneous abortions. One was a tubal pregnancy; one terminated electively. One resulted in a miscarriage in the 15th gestational week; the fetus suffered form a complex cardiac malformation. All newborns, except one, who was born with hexadactyly, were healthy. Of 51 terminated pregnancies 22 women had (4/12/9/trimester) relapses during pregnancy; and 4 were again with natalizumab during pregnancy. 3 of these 4 treated newborns showed haematological noticeable problems after delivery, resolving during the first weeks. Natalizumab could be detected in one of the newborns analysing the concentration in the umbilical cord, indicating that there is a transport to the fetus. The finalized dataset will be presented at the time of the meeting. Conclusions: If treatment with natalizumab is necessary during the second or third trimester, the newborns should be monitored closely after birth. Additional safety data of natalizumab exposure during pregnancy are needed to exclude any major teratogenic and/or pro-abortive risk. Supported by: The German MS and pregnancy registry was partly supported by Bayer Healthcare, Biogen Idec Germany, Merck Serono, Teva Sanofi Aventis and Novartis. Disclosure: Dr. Hellwig has received personal compensation for activities with Bayer Phramceuticals Corporation, Schering AG, Biogen Idec, Merck Serono, Teva Neuroscience, Aventis Phramceuticals Corporation and Novartis as a speaker.Dr. Hellwig has received research support from Bayer Phramceuticals Corporation, Schering AG, Biogen Idec, Serono, Novartis and Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc. Dr. Haghikia has nothing to disclose. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience.

MINI Mental MUltiple Sclerosis Examination (MINIMUS): Neuropsychological Screening for MS Patients (P04.112)

Objective: To assess the ability of a short version of the BRB to identify cognitive impairment(CI)in multiple sclerosis(MS). Background The search for a screening of CI in MS is a major undertaking. Recently it has been suggested that three tests of the Brief Repeatable Battery(BRB)can obtain good levels of sensitivity, specificity and accuracy. Design/Methods: We included all the neuropsychological assessments consecutively carried out in six Italian MS Centres. All the patients were diagnosed with MS, aged 18-65 years, and had adequate vision and hearing to undergo the tests. Cognitive performance was assessed through the BRB and the Stroop Test(ST). Failure of a test was defined on the basis of the Italian normative values. CI was defined as the failure of at least 2 tests. Bayesian statistics predicting CI patients were calculated for each test. Results: 1040 Relapsing-Remitting MS patients were included. CI was detected in 467(47%) patients. The tests with higher sensitivity in detecting CI were the Paced Auditory Serial Addition Test(PASAT-3: sensitivity=63.6%;95%CI59.0-68.1), the Symbol Digit Modalities Test (SDMT; sensitivity=57.8;95%CI53.3-62.3), the Word List Generation (WLG: sensitivity=52.4;95%CI47.5-57.3) and the Selective Reminding Test (Long Term Storage -LTS: sensitivity=37.8;95%CI33.3-42.1; Consistent Long Term Retriveal-CLTR: sensitivity=42.4;95%CI37.9-46.9). These tests were combined into four short batteries. The highest sensitivity and accuracy were obtained by the battery including the SRT-LTS, the SRT-CLTR, the PASAT-3 and the SDMT (sensitivity=94.4%; Specificity=84,7%; Accuracy=89.0%). Psychometric properties remained good also for the battery in which the WLG was included instead of the PASAT-3 (Sensitivity=88.4%; Specificity=79,1%, Accuracy=83.4%). This battery requires approximately 12 minutes for administration and no special equipment. Conclusions: In the present study we propose a brief battery based on a short version of the BRB and ST, that may represent a suitable and cost effective tool for screening of MS-related CI. Supported by: In part by Biogen Dompe. Disclosure: Dr. Amato has received personal compensation for activities with Merck Serono, Biogen Dompe, Sanofi-Aventis Pharmaceuticals, and Bayer Schering. Dr. Amato has received research support from Merck Serono, Sanofi-Aventis Pharmaceuticals, Biogen Dompe, and Bayer Schering. Dr. Goretti has nothing to disclose. Dr. Portaccio has received personal compensation for activities with Biogen Idec as an advisory board member.Dr. Portaccio has received research support from Biogen Idec, Merck Serono, Sanofi Aventis, and Bayer Schering Dr. Patti has received personal compensation for activities with Merck-Serono, Bayer Schering, and Dompe Biotec. Dr. Cilia has nothing to disclose. Dr. Gallo has nothing to disclose. Dr. Grossi has nothing to disclose. Dr. Viterbo has received personal compensation for activities with Biogen Idec and Novartis. Dr. Ghezzi has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation and Sanofi-Aventis Pharmaceuticals, Inc. as a speaker. Dr. Roscio has nothing to disclose. Dr. Mattioli has nothing to disclose. Dr. Stampatori has nothing to disclose. Dr. Trojano has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Sanofi-Aventis Pharmaceuticals, Inc. as a consultant and/or speaker. Dr. Trojano has received research support from Merck & Co., Inc.

Monthly Pulse Adrenocorticotropic Hormone (ACTH) or Methylprednisolone Therapy for Long-Term Treatment of Multiple Sclerosis as an Add-On Therapy to beta-Interferons: Current Status of the Pilot Study (P04.147)

Objective: This pilot study is designed to evaluate the efficacy and safety of monthly adrenocorticotropic hormone (ACTH) treatment added to beta-interferon in breakthrough multiple sclerosis (MS) compared with monthly methylprednisolone (MP), the most commonly used therapy. Background ACTH gel is approved for treatment of MS relapses. There is mounting evidence that ACTH may have a variety of immune-modulating mechanisms relevant to the MS disease course. However, no clinical studies have evaluated ACTH pulse therapy for MS. Design/Methods: This single-center, examiner-blinded study enrolled MS patients receiving ongoing beta-interferon treatment with Expanded Disability Status Scale (EDSS) scores of 3.0-6.5 and ≥1 relapse or new T2 or Gadolinium-enhanced lesion within the previous year. Patients were randomly assigned to open-label ACTH (80 units intramuscularly once/day x 3 consecutive days) or MP (1 gram IV x 1 dose) monthly for 12 months, with assessments every 3 months. Outcomes include relapse rate (primary); EDSS, MS Functional Composite, and MS Quality of Life scores; MRI; bone density; and side effects. We report the current status of the study. Results: Of 26 patients enrolled (ACTH: n=14, mean±SD EDSS 4.4±1.4; MP: n=12, mean EDSS 4.7±1.4), 18 have ≥6 months of data (ACTH: n=10, MP: n=8). During 6 months of pulse therapy, there were 0 relapses in the ACTH group and 4 relapses (in 2 patients) in the MP group. Mean EDSS score at month 3 was 3.9±2.0 (p=0.028; n=12) for ACTH and 3.9±1.6 (p=0.058; n=10) for MP. EDSS at month 6 was 4.4±1.8 (p=0.075) for ACTH and 4.2±2.0 (p=0.401) for MP. Seventeen side effects were reported from 9 patients in the ACTH group and 13 side effects were reported by 6 patients in the MP group. Conclusions: These data suggest a potential role for ACTH pulse therapy in treating breakthrough MS. Supported by: Questcor Pharmaceuticals, Inc. Disclosure: Dr. Berkovich has received personal compensation for activities with Acorda Therapeutics, Bayer Pharmaceuticals Corporation, Biogen Idec, Teva Neuroscience and Questcor Inc. as a speaker. Dr. Berkovich has received research support from Questcor Inc. Dr. Amezcua has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Teva Neuroscience, and Serono/Pfizer Inc. Dr. Fernandez has nothing to disclose. Dr. Subhani has nothing to disclose. Dr. Kravtsova has nothing to disclose.

Natalizumab Treatment Effects Sustained Decrease in Serum Levels of Fibronectin and Soluble Adhesion Molecules sVCAM-1 and sICAM-3 (P02.114)

Objective: To obtain a better understanding of potential additional effector mechanisms of natalizumab we analyzed the influence of short and long-term treatment on soluble adhesion molecules (sAMs) in peripheral blood of MS patients. Background Natalizumab (Tysabri) is a humanized monoclonal antibody used in the treatment of relapsing-remitting multiple sclerosis (MS). It directly binds to the alpha4-integrin subunit of very late activation antigen-4 (VLA-4) and results in decreased detectability of unblocked alpha-4 leading to an inhibition of immune cell extravasation across the blood-brain-barrier. The impressive therapeutic effect of natalizumab is overshadowed by rare but potentially serious side effects such as progressive multifocal leukoencephalopathy. Design/Methods: Serum levels of fibronectin (FN) and 4 different sAMs (soluble intercellular adhesion molecule-1,-2,-3 (sICAM-1,-2,-3) and vascular cell adhesion molecule-1 (sVCAM-1)) were analyzed before (baseline, n=16), 3 months after (short-term, n=16) and 24 months after (long-term, n=14) onset of Natalizumab treatment by fluorescent bead immunoassay and enzyme-linked immunosorbent assay. Results: A significant and sustained decrease in serum concentrations of FN, sICAM-3 and sVCAM-1 was observed during the first 3 months (FN p Conclusions: The observed decreases in serum levels highlight sICAM-3, sVCAM-1, and FN to be affected by natalizumab therapy. Decreases in sVCAM-1 serum levels have already been previously reported. We add sICAM-3 and the soluble form of the extracellular matrix protein FN. Both, sVCAM-1 and FN have been shown to be directly engaged in VLA-4-mediated extravasation of immune cells and sICAM-3 is important in the initiation of immune responses. Decreased serum levels indicate potential therapy-induced interference with fine-tuning and/or feedback mechanisms between endothelium and immune cells with yet unresolved consequences. Supported by: Biogen-Idec Austria. Disclosure: Dr. Kraus has received personal compensation for activities with Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck-Serono, Novartis, Genzyme Corporation as a consultant. Dr. Kraus has received research support from Biogen Idec, Bayer Pharmaceuticals Corporation, Sanofi-Aventis Pharmaceuticals, Merck Serono, Novartis, Genzyme Corporation. Dr. Oppermann has nothing to disclose. Dr. Pilz has nothing to disclose. Dr. Wipfler has nothing to disclose. Dr. Afazel has nothing to disclose. Dr. Haschke-Becher has nothing to disclose. Dr. Trinka has received personal compensation for activities with UCB Pharma, Eisai Inc., Sunovion, Medtronic, Pfizer Inc, Ever-Neuropharma and GlaxoSmithKline, Inc. as a consultant and/or speaker. Dr. Trinka has received research support from UCB Pharma, Ever-Neuropharma, Medtronic and GlaxoSmithKline, Inc. Dr. Harrer has nothing to disclose.