Search

Background and ObjectivesIn MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatment have been linked to immunosenescence, a state of cellular dysfunction associated with chronic inflammation.MethodsTo evaluate age-related immunologic alterations in MS, we compared immune signatures in peripheral blood (PB) and CSF by flow cytometry in patients with relapsing-remitting (RR) (PB n = 38; CSF n = 51) and primary progressive (PP) MS (PB n = 40; CSF n = 36) and respective controls (PB n = 40; CSF n = 85).ResultsAnalysis revealed significant age-related changes in blood immune cell composition, especially in the CD8 T-cell compartment of healthy donors (HDs) and patients with MS. However, HDs displayed a strong age-dependent decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells, whereas this age-dependent reduction was completely abrogated in patients with MS. An age-dependent increase in the expression of the costimulatory molecule CD226 on memory CD8 T cells was absent in patients with MS. CD226 expression correlated with disability in younger (≤50 years) patients with MS. CSF analysis revealed a significant age-dependent decline in various immune cell populations in PPMS but not RRMS, suggesting a differential effect of aging on the intrathecal compartment in PPMS.DiscussionOur data illustrate that aging in MS is associated with a dysbalance between costimulatory and immunoregulatory signals provided by CD8 T cells favoring a proinflammatory phenotype and, more importantly, a pattern of premature immune aging in the CD8 T-cell compartment of young patients with MS with potential implications for disease severity.

To investigate the association of combined serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements with future disease activity in patients with early multiple sclerosis (MS).We analyzed sNfL by single molecule array technology and performed OCT measurements in a prospective cohort of 78 patients with clinically isolated syndrome and early relapsing-remitting MS with a median (interquartile range) follow-up of 23.9 (23.3-24.7) months. Patients were grouped into those with abnormal or normal sNfL levels, defined as sNfL ≥/80th percentile of age-corrected reference values. Likewise, patients were grouped by a median split into those with thin or thick ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer, and inner nuclear layer in nonoptic neuritis eyes. Outcome parameters were violation of no evidence of disease activity (NEDA-3) criteria or its components.Patients with abnormal baseline sNfL had a higher risk of violating NEDA-3 (hazard ratio [HR] 2.28, 95% CI 1.27-4.09,In patients with early MS, the presence of both abnormal sNfL and thin GCIP is a stronger risk factor for future disease activity than the presence of each parameter alone.

Alemtuzumab is a humanized monoclonal antibody that causes a rapid but long-lasting depletion of the CD52-bearing lymphoid lineage. Selective pulsed depletion is followed by a complex pattern of immune cell reconstitution that reflects the reshaping and potential reprogramming of immune networks, including the development of tolerance.1 Recent studies showed that pulsed-immune reconstitution therapy with alemtuzumab can produce durable efficacy after 2 courses of treatment (year 1 and 2).2–5

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) have developed tremendously over the last 2 decades. Currently, more than 16 different products targeting various immunologic components have been approved for MS treatment in several countries. The authors thank Heike Blum for drawing the figure and Nick Fulcher for language editing.

On behalf of all authors, we would like to thank Mr. Tugemann for his interest in our article.1 It is correct that acute progressive multifocal leukoencephalopathy (PML) can, in some circumstances, lead to high(er) CD62L values. However, as the study was conducted prospectively and, more importantly, alongside treatment, we reported all results of samples shipped to us back to the treating physicians. At the time of measurement and reporting, we were not aware of the patients' disease state. Because this is the situation to be expected in postmarketing settings, we chose to report all measured values, even if the samples turned out to be less than 6 months before PML diagnosis. Although the exclusion of these samples would indeed have led to a perfect sensitivity with the threshold of 36.05, we believed that it would not accurately reflect the real-world situation. Similarly, we chose not to focus on other PML risk stratification factors such as previous immune suppression or anti-JC virus antibody serostatus because we could not rely on having this information for all samples shipped to us. We, therefore, decided to report on the feasibility of measuring one biomarker rather than presenting a holistic approach for risk stratification using all available markers, which was addressed before.2 As supported by this study, CD62L was proven to be a useful biomarker for PML risk stratification also in the real-world setting but could also help with monitoring immunologic changes because of natalizumab-extended interval dosing. Owing to its initial detection in a retrospective cohort, the validated methodology3 still requires a mandatory freeze/thaw cycle, thereby limiting its widespread use. However, we would be more than happy if methodological improvements could be achieved here.

ObjectiveTo provide first real-world experience on patients with MS treated with the B cell–depleting antibody ocrelizumab.MethodsWe retrospectively collected data of patients who had received at least 1 treatment cycle (2 infusions) of ocrelizumab at 3 large neurology centers. Patients' characteristics including premedication, clinical disease course, and documented side effects were analyzed.ResultsWe could identify 210 patients (125 women, mean age ± SD, 42.1 ± 11.4 years) who had received ocrelizumab with a mean disease duration of 7.3 years and a median Expanded Disability Status Scale score of 3.75 (interquartile range 2.5–5.5; range 0–8). Twenty-six percent of these patients had a primary progressive MS (PPMS), whereas 74% had a relapsing-remitting (RRMS) or active secondary progressive (aSPMS) disease course. Twenty-four percent of all patients were treatment naive, whereas 76% had received immune therapies before. After ocrelizumab initiation (median follow-up was 200 days, range 30–1,674 days), 13% of patients with RRMS/aSPMS experienced a relapse (accounting for an annualized relapse rate of 0.17, 95% CI 0.10–0.24), and 5% of all patients with MS experienced a 12-week confirmed disability progression. Treatment was generally well tolerated, albeit only short-term side effects were recorded, including direct infusion-related reactions and mild infections.ConclusionsWe provide class IV evidence that treatment with ocrelizumab can stabilize naive and pretreated patients, indicating that ocrelizumab is an option following potent MS drugs such as natalizumab and fingolimod. Further studies are warranted to confirm these findings and to reveal safety concerns in the longer-term follow-up.Classification of evidenceThis study provides Class IV evidence that for patients with MS, ocrelizumab can stabilize both treatment-naive and previously treated patients.

Background and Purpose— T lymphocytes have recently been identified as key mediators of tissue damage in ischemic stroke. The interaction between very late antigen-4 (VLA-4) and vascular adhesion molecule-1 is crucial for the transvascular egress of T lymphocytes, and inhibition of this interaction by specific antibodies is a powerful strategy to combat autoimmune neuroinflammation. However, whether pharmacological blocking of T-lymphocyte trafficking is also protective during brain ischemia is still unclear. We investigated the efficacy of a monoclonal antibody directed against VLA-4 in mouse models of ischemic stroke. Methods— Transient and permanent middle cerebral artery occlusion was induced in male C57Bl/6 mice. Animals treated with a monoclonal anti-CD49d antibody (300 μg) 24 hours before or 3 hours after the onset of cerebral ischemia and stroke outcome, including infarct size, functional status, and mortality, were assessed between day 1 and day 7. The numbers of immune cells invading the ischemic brain were determined by immunocytochemistry and flow cytometry. Results— Blocking of VLA-4 significantly reduced the invasion of T lymphocytes and neutrophils on day 5 after middle cerebral artery occlusion and inhibited the upregulation of vascular adhesion molecule-1. However, the anti-CD49d antibody failed to influence stroke outcome positively irrespective of the model or the time point investigated. Conclusions— Pharmacological inhibition of the VLA-4/vascular adhesion molecule-1 axis in experimental stroke was ineffective in our hands. Our results cast doubt on the effectiveness of anti-CD49d as a stroke treatment. Further translational studies should be performed before testing anti–VLA-4 antibodies in patients with stroke.

Alemtuzumab is an efficacious therapy for active relapsing-remitting MS (RRMS), but its use is complicated by the potential development of secondary autoimmunity.1 Recent data from phase 3 extension studies confirm thyroid autoimmunity as the most abundant entity of secondary autoimmunity found in up to 30%–40% of treated patients, with most events mild or moderate in severity. Data also show low rates of previously known autoimmune phenomena, such as immune thrombocytopenia and nephropathy.2 However, further entities including sarcoidosis, vitiligo, and hemophagocytic lymphohistiocytosis (HLH) have been described in real-world cohorts.3 Here, we present a case of another lymphoproliferative syndrome, namely idiopathic multicentric Castleman disease (iMCD), after alemtuzumab treatment.

Purpose of review Autoimmune diseases are the result of an imbalanced immune regulatory network. Tolerogenic dendritic cells (tolDCs) are key players of this network by inducing and maintaining both central and peripheral tolerance. Therefore, ex vivo generated tolDCs are considered as therapeutic vaccines to re-establish (antigen-specific) tolerance in autoimmune disorders. Recent findings TolDCs represent a heterogeneous group of dendritic cells that reside in different tissues and maintain tolerance by inducing anergy or apoptosis of autoreactive T cells, phenotypic skewing and induction of different types of regulatory T cells (Tregs). Both experimental animal models of autoimmune diseases and in vitro experiments with ex vivo generated human tolDCs have demonstrated their potency in re-establishing antigen-specific tolerance. The identified key mechanisms are induction of antigen-specific T cell anergy and/or promoting Tregs. Summary TolDCs represent an interesting strategy to re-establish antigen-specific tolerance and thus are considered as a treatment option for autoimmune diseases. First clinical trials are on the way. However, several technical and conceptual difficulties exist, ranging from the choice of antigen(s), dendritic cell generation protocols, to application regimens. This review discusses the state of this therapeutic concept including chances, perils and pitfalls.

Objective: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease. Methods: We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies. Results: In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients9 peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve-infiltrating CD8+ T-cell clones was visualized by immunohistochemistry. Conclusions: Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP.

This review focuses on advances in current and novel treatment approaches in multiple sclerosis.New therapeutic approaches in multiple sclerosis are emerging. Orally available treatment strategies are more acceptable for patients and may improve adherence to therapy. An oral formulation of glatiramer acetate failed to demonstrate efficacy in a clinical trial, but other promising compounds are on the horizon, such as FTY720. Advances are currently being made in use of therapeutic monoclonal antibodies that specifically target key molecules involved in the immunopathogenesis of multiple sclerosis. Natalizumab directed against the adhesion molecule very late antigen-4 represents the first specific antibody to be added to our therapeutic armamentarium for multiple sclerosis. Further evidence that immunomodulation should be initiated as early as possible has been reported.Treatment of multiple sclerosis has changed dramatically over the past decade. Enhanced understanding of the immunopathological processes that underlie the disease, advances in biotechnology and development of powerful magnetic resonance imaging technologies, together with improvements in clinical trial design have led to a variety of valuable therapeutic approaches, which are currently being studied in detail.

The aim of this review is to describe the local immune circuitry in the peripheral nervous system and its dialogue with systemic immunity under pathological conditions. Specifically, interactions of the immune system with cellular and extracellular components within peripheral nerve and immune functions of tissue-resident endoneurial macrophages and Schwann cells will be discussed.New insights into the elements involved in the pathogenesis of immune-mediated disorders of the peripheral nervous system provide a better understanding of the complex interplay of these cellular and molecular components in the immunology of the peripheral nervous system.The application of innovative and cutting-edge technologies to the study of immunoinflammatory disorders of the peripheral nervous system provides a better understanding of underlying principles of the organization of the immune network present in the peripheral nerve and its dialogue with the systemic immune system. This may foster the development of specific and highly effective therapies for immune-mediated disorders of the peripheral nerve.

Alemtuzumab is an effective therapeutic option for patients with active forms of relapsing-remitting multiple sclerosis (RRMS).1 The adverse event profile comprises an increased risk for the development of secondary autoimmune disorders as well as infusion-associated reactions. Alemtuzumab infusion is often associated with an acute cytokine release syndrome.2 Among other side effects, patients may experience headache, rash, pyrexia, and to a lesser extent hypotension, cardiac arrhythmia, and rarely anaphylactic shock. These symptoms are usually limited to the first days of infusion and do not lead to sustained impairment.1

Editors' Note: Commenting on “Natalizumab-related PML 2 weeks after negative anti-JCV antibody assay” Ontaneda and Fox suggest, backed by analysis of progressive multifocal leukoencephalopathy (PML) cases with fingolimod and dimethyl fumarate, that age is a potential risk for PML in patients with multiple sclerosis (MS) and that age should be assessed as a risk stratifier for PML with MS therapies. Gagne Brosseau et al., authors of the initial report, agree and give additional clarification regarding the relation between age and JC virus. Schwab et al. disagree with “CD62L is not a reliable biomarker for predicting PML risk in natalizumab-treated R-MS patients,” pointing to how tested samples appear to be compromised and how the assay was changed from published protocols. Cahir-McFarland et al., authors of the study, explain why CD62L is not a reliable biomarker for PML risk, why the assay was changed, and that the samples were not compromised but reflect the differences between CD62L count in healthy volunteers vs patients with MS or natalizumab-treated patients. —Chafic Karam, MD, and Robert C. Griggs, MD Cells for the study …

Objective:To describe the time course of α4-integrin receptor desaturation and disease activity return in patients with relapsing-remitting MS who discontinued natalizumab and to investigate baseline and on-study predictors for the recurrence of disease activity.Methods:In the course of TOFINGO, a 32-week, patient- and rater-blinded multicenter, parallel-group study, we performed MRI, counted relapses, and measured α4-integrin receptor occupancy (RO) at baseline and 8, 12, 16, 20, and 24 weeks. The relationship between RO and total number of new T1 gadolinium-enhancing (Gd+) lesions was modeled using Poisson linear regression.Results:Patients (N = 142) were randomized (1:1:1) to 8-, 12-, or 16-week washout (WO) groups. At randomization, the median RO in the 8-, 12-, and 16-week WO groups was 94.5%, 92.4%, and 90.9%, which declined to 79.8%, 30.7%, and 8.7% after 8, 12, and 16 weeks of WO, respectively. The percentage of patients with new T1 Gd+ lesions increased with longer WO period before commencing fingolimod: 2.1% (8 weeks), 9.1% (12 weeks), and 50.0% (16 weeks). Overall, 71% of patients with first relapse between weeks 6 and 18 had RO values below the time-matched population median. Higher T2 lesion volume (LV) at baseline predicted a higher number of new T1 Gd+ lesions.Conclusions:A faster decline in natalizumab RO, longer WO period, and higher T2 LV at baseline were associated with an increased risk for return of inflammatory disease activity. These results provide a mechanistic rationale and, together with the main outcomes of the TOFINGO study, support initiation of fingolimod within 8 weeks of natalizumab discontinuation.ClinicalTrials.gov identifier:NCT01499667.

We thank Elkins et al1 for their interest in our study2 and their thoughtful comments. We fully agree that preclinical stroke models can only mimic certain aspects of this heterogeneous disease and the decision to enter into clinical trial programs should not only depend on the results from animal studies albeit the predictive value of experimental stroke studies is probably better than previously perceived.3 In fact, based on our neutral findings regarding the efficacy of blocking very late antigen-4 (VLA-4) in mouse models of brain ischemia,2 we never claimed to halt or delay the ongoing Phase 2 ACTION trial (NCT01955707) testing natalizumab in patients with ischemic stroke. Instead, we think that modulating the immune system could become an attractive strategy to positively influence stroke outcome,2 and we appreciate the …

For many years ischemic stroke was regarded as a purely thrombotic disease resulting from the occlusion of cerebral arteries and subsequent breakdown of energy supply to neuronal tissues. Back in the late 1970, however, some pioneers in experimental stroke research, above all John Hallenbeck at the National Institute of Neurological Disorders and Stroke recognized the existence of polymorphonuclear leukocytes and macrophages in brain specimen from animals and patients with cerebral ischemia, thereby establishing the conceptual basis for the immunobiology of stroke.1 Since then a plethora of experimental studies stressed the importance of these typically innate immune cells in brain ischemia but clinical trials testing, for example, neutrophil blocking agents, ultimately bombed. Several years later Stoll and Jander2 from Dusseldorf, Germany, were among the first to describe the infiltration of T lymphocytes, which per definition belong to the adaptive immune system, into ischemic brains of rodents. Of note, this happened accidentally while searching for a central nervous system lesion paradigm devoid of inflammation which could be used as control for experimental …

Objective: To characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment. Methods: Circulating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)–23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined. Results: In comparison to CD4 + T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56 bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change. Conclusions: Our findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56 bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56 bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS.

Objectives: To characterize the cellular autoimmune response in patients with γ-aminobutyric acid (GABA) B receptor antibody–associated limbic encephalitis (GABA B -R LE). Methods: Patients underwent MRI, extensive neuropsychological assessment, and multiparameter flow cytometry of peripheral blood and CSF. Results: We identified a series of 3 cases of nonparaneoplastic GABA B -R LE and one case of paraneoplastic GABA B -R LE associated with small cell lung cancer. All patients exhibited temporal lobe epilepsy, neuropsychological deficits, and MRI findings typical of LE. Absolute numbers of CD19 + B cells, CD138 + CD19 + plasma cells, CD4 + T cells, activated HLADR + CD4 + T cells, as well as CD8 + T cells and HLADR + CD8 + T cells did not differ in peripheral blood but were elevated in CSF of patients with GABA B -R LE compared to controls. Augmented absolute numbers of CD138 + CD19 + plasma cells and activated HLADR + CD8 + T cells in CSF corresponded to higher overall neuropsychological and memory deficits in patients with GABA B -R LE. A histologic specimen of one patient following selective amygdalohippocampectomy revealed perivascular infiltrates of CD138 + plasma cells and CD4 + T cells, whereas cytotoxic CD8 + T cells were detected within the brain parenchyma in close contact to neurons. Conclusion: Our data suggest a pathogenic role for CD8 + T cells in addition to the established role of plasma cell–derived autoantibodies in GABA B -R LE.

Objective: To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4 + and CD8 + T cell subsets in patients with multiple sclerosis (MS). Methods: Peripheral lymphocyte subsets, including CD4 + and CD8 + memory cells and T helper (T H ) cells T H 1, T H 2, T H 17, and peripheral regulatory T cell (pT reg ) subpopulations were analyzed before and 6 months after onset of DMF treatment. Results: CD4 + and CD8 + memory T cells were preferentially decreased compared to naive CD4 + and CD8 + T cell populations. Within the CD4 + memory T cell population, frequencies of T H 1 cells were decreased, whereas those of T H 2 cells were increased and those of T H 17 cells remained unaltered. Accordingly, we observed decreased production of interferon γ, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor α, and interleukin (IL)-22 by CD4 + T cells under DMF treatment, whereas the frequency of IL-4- and IL-17A-producing CD4 + T cells remained unchanged. With regard to regulatory T cells, proportions of pT reg increased following DMF treatment. Conclusion: Our data demonstrate that DMF treatment of patients with MS affects predominantly memory T cells accompanied by a shift in T H cell populations, resulting in a shift toward anti-inflammatory responses. These findings indicate that monitoring of memory subsets might enhance vigilance of impaired antiviral immunity and that patients with T H 1-driven disease might preferentially benefit from DMF treatment. Classification of Evidence: This study provides Class IV evidence that DMF might preferentially reduce CD4 + and CD8 + memory T cells in MS.

Objective: To evaluate immune responses to neoantigen and recall antigens in healthy subjects treated with teriflunomide. Methods: This was a randomized, double-blind, placebo-controlled study. Subjects received oral teriflunomide (70 mg once daily for 5 days followed by 14 mg once daily for 25 days) or placebo for 30 days. Antibody responses were evaluated following rabies vaccination (neoantigen) applied at days 5, 12, and 31 of the treatment period. Occurrence of delayed-type hypersensitivity (DTH) to Candida albicans, Trichophyton, and tuberculin (recall antigens) was assessed before and at the end of treatment to investigate cellular memory response. Safety and pharmacokinetics were evaluated. Results: Forty-six randomized subjects were treated (teriflunomide, n = 23; placebo, n = 23) and completed the rabies vaccination. Geometric mean titers for rabies antibodies were lower with teriflunomide at days 31 and 38 than with placebo. However, all subjects achieved sufficient seroprotection following rabies vaccination (titers well above the 0.5 IU/mL threshold). Overall, the DTH response to recall antigens in the teriflunomide group did not notably differ from responses in the placebo group. Conclusions: Following vaccination, geometric mean titers for rabies antibodies were lower with teriflunomide than with placebo. However, teriflunomide did not limit the ability to achieve seroprotective titers against this neoantigen. Evaluation of DTH showed that teriflunomide had no adverse impact on the cellular memory response to recall antigens. Classification of evidence: This study provides Class II evidence that in normal subjects treated with teriflunomide, antibody titer responses to rabies vaccination are lower than with placebo but sufficient for seroprotection.

Pregnancy in multiple sclerosis (MS) has been controversial. For years women with MS were discouraged from considering pregnancy.1,2 The Pregnancy in Multiple Sclerosis (PRIMS) study in Europe provided the first robust data on the influence of pregnancy and delivery on the clinical course of MS.3 It demonstrated a decline in relapse rate during pregnancy, most marked in the third trimester, with a rebound increase in the first 3 months postpartum. Breastfeeding did not show any specific effect on the clinical course after delivery. A 2-year postpartum follow-up of the PRIMS patient cohort corroborated these findings.4 These results changed the prevailing view on the general risk of pregnancy in women with MS. It is now generally accepted that pregnancy per se cannot be regarded as a risk factor in patients with MS.5 That breastfeeding has no impact on clinical relapse activity postpartum was recently challenged by a prospective cohort study conducted by Langer-Gould and colleagues6 in California. They reported that women with MS who breastfed exclusively for the first 2 months postpartum were approximately one-fifth …

Natalizumab (Tysabri®, Biogen Idec Inc., Cambridge, MA) is a recombinant humanized monoclonal antibody that binds to the α4 chain of the integrin very late activation antigen (VLA)-4 and to α4β7 integrin. It was designed to diminish the adherence of activated leukocytes to biologic membranes and their subsequent migration into peripheral tissues, including the brain and the spinal cord. The clinical effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (MS) was evaluated in 2 phase 3 clinical trials (the AFFIRM monotherapy trial1 and the SENTINEL add-on trial with interferon beta-1a [Avonex®, Biogen Idec Inc.]2). In the United States, the Food and Drug Administration first approved natalizumab on November 24, 2004, for the treatment of relapsing forms of MS. Only 3 months later, the manufacturers of natalizumab announced its voluntary withdrawal after 2 patients with MS and 1 patient with Crohn disease who had received natalizumab in clinical trials were diagnosed with progressive multifocal leukoencephalopathy (PML).3–5 PML, a brain demyelinating disorder caused by the human polyomavirus JC, is almost exclusively diagnosed in individuals who experience severe and prolonged immunosuppression. The occurrence of PML in patients with MS treated with natalizumab was unexpected to many because there …

Objective: Evaluate long-term safety, efficacy, and associations between baseline treatment history and postbaseline annualized relapse rate (ARR) in multiple sclerosis (MS) patients treated with natalizumab. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) study is an open-label, multinational, observational study assessing long-term outcomes in relapsing-remitting MS patients in the postmarketing setting in Europe, Australia, and Canada. Design/Methods: As of June 2011, 3484 patients from 15 countries were enrolled. Incidence of serious adverse events (SAEs) was analyzed. ARR and Expanded Disability Status Scale (EDSS) scores were assessed. Associations between baseline therapy and postbaseline ARR were analyzed using negative binomial regression for 5 baseline groups: therapy naive (n=337), interferon (IFN) only (n=1626), glatiramer acetate (GA) only (n=288), switched between GA and IFN in either order (n=595), or immunosuppressant (IS) use (n=487). Results: - 53]) natalizumab infusions. Overall, 5.1% of patients experienced ≥1 SAE; infections (1.1%) and hypersensitivity reactions (0.7%) were most frequent. Seven cases of progressive multifocal leukoencephalopathy (PML) occurred after 35, 29, 28, 26, 24, 24, and 12 natalizumab infusions. Three of them were previously exposed to mitoxantrone. Overall, the mean EDSS score was 3.5 at baseline and 3.4 after 3 years. ARR was significantly decreased regardless of baseline treatment history; mean ARR decreased (n=3458) from baseline (1.98) to postbaseline (0.28; P Conclusions: The overall incidence and type of SAEs reported in TOP are consistent with natalizumab9s known safety profile. EDSS scores were stable and ARR was significantly reduced after 3 years of natalizumab therapy. ARRs were lowest in therapy-naive patients and highest in patients with prior IS. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. 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. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. 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. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.

Objective: Evaluate geographic region, enrollment time, baseline characteristics, postbaseline efficacy, and safety in natalizumab-treated multiple sclerosis (MS) patients with and without prior treatment. Background The ongoing natalizumab (TYSABRI®) Observational Program (TOP) assesses long-term outcomes in natalizumab-treated patients with relapsing-remitting MS in Europe, Australia, and Canada. Design/Methods: Baseline characteristics of treatment-naive and previously treated patients were compared. The association between prior treatment status and postbaseline annualized relapse rates (ARRs) was examined using a negative binomial regression model. Time to improvement on the Expanded Disability Status Scale (EDSS) was analyzed using a Cox proportional hazards model. Serious adverse events (SAEs) were compared using a Pearson chi-square or Fisher exact test. Results: As of June 1, 2011, 337 of 3484 natalizumab-treated patients (10%) had been treatment naive before natalizumab treatment. Proportions of treatment-naive patients varied significantly by country (Slovakia, 0%; Great Britain, 36%) and time since enrollment (0–12 months, 12%; 13–24 months, 7%; >24 months, 9%). Baseline differences between treatment-naive and previously treated patients included mean age (35.8 vs 37.6 years), median disease duration (1.9 vs 7.8 years), and median EDSS score (3.0 vs 3.5) (all P ≤0.013). Treatment-naive patients had a lower postbaseline ARR (0.18 vs 0.26; P =0.002) and were more likely to show improvement in EDSS at 3 years (HR [95% confidence interval]=1.59 [1.14–2.22]; P =0.007). Treatment-naive and previously treated groups did not significantly differ in incidence of SAEs (4.2% vs 5.2%; P =0.340), infection-related SAEs (0.9% vs 1.2%; P =0.640), or progressive multifocal leukoencephalopathy (0.0% vs 0.2%; P =1.00). Conclusions: Treatment-naive patients were younger than previously treated patients, had shorter disease duration and lower baseline EDSS, were more likely to show EDSS improvement, and differed significantly in geographic distribution and enrollment time. While relapses decreased in both groups, postbaseline ARR was significantly lower in treatment-naive patient, whereas SAE incidence was similar. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Butzkueven has received personal compensation for activities with Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, Inc., National Health and Medical Research Council, and National MS Society. Dr. Butzkueven has received personal compensation in an editorial capacity for Multiple Sclerosis International Federation and Multiple Sclerosis. Dr Butzkueven has received research support from Biogen Idec, Merck Serono, and Novartis. Dr. Belachew has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec and Merck Serono as a consultant. Dr. Belachew has received research support from Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis Pharmaceuticals, and Teva Neuroscience. 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. Pellegrini has received personal compensation for activities with Biogen Idec as a consultant. 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. Dr. Wiendl has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Wiendl has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Medac, Merck-Serono, Novo Nordisk, Sanofi-Aventis Pharmaceuticals, Inc., Schering AG and Teva Neuroscience. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator.