Augusto Miravalle

Immune Reconstitution Inflammatory Syndrome in Patients With Multiple Sclerosis Following Cessation of Natalizumab Therapy

OBJECTIVE To assess clinical consequences of temporary natalizumab dosage suspension. DESIGN Prospective cohort study. SETTING Multiple sclerosis (MS) center at an academic medical center in the United States. PATIENTS Thirty-two patients with MS who had received at least 12 consecutive natalizumab infusions. MAIN OUTCOMES MEASURES Recurrent MS disease activity, defined as a clinically documented exacerbation with objective findings and/or the development of 1 or more new gadolinium-enhancing lesions on magnetic resonance imaging. RESULTS Thirty-eight percent of patients with relapsing-remitting and secondary progressive MS experienced relapses during therapy interruption or shortly after restarting natalizumab therapy (9 of 24 and 3 of 8, respectively), but relapses were severe with unusually widespread evidence of inflammatory activity on magnetic resonance imaging in several patients with secondary progressive MS with greater inflammatory disease activity prior to starting natalizumab therapy. Imaging and cerebrospinal fluid findings in these cases were suggestive of an immune reconstitution inflammatory syndrome. Overall, relapses occurred more often in younger patients with fewer natalizumab infusions prior to therapy interruption. The number of gadolinium-enhancing lesions at the time of relapse after therapy interruption was modestly correlated with the number of gadolinium-enhancing lesions prior to starting natalizumab therapy (r = 0.51; P = .45). Prior disease control resumed after reinstitution of natalizumab therapy in all patients. CONCLUSIONS In this cohort of patients with MS who had disease refractive to multiple therapeutics before starting natalizumab treatment, magnetic resonance imaging and clinical disease activity returned, often aggressively, following discontinuation of natalizumab therapy. These findings suggest we should consider strategies to minimize the risk of immune reconstitution inflammatory syndrome after natalizumab discontinuation.

Update on PML and PML-IRIS Occurring in Multiple Sclerosis Patients Treated With Natalizumab

Abstract The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction–based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria.

Recent insights into the mechanism of action of glatiramer acetate

Glatiramer acetate (GA, Copaxone®, co-polymer 1) is an immunomodulatory therapy approved in 1996 by the United States Food and Drug Administration for treatment of relapsing-remitting multiple sclerosis. GA has a good safety profile, moderate efficacy, and a unique mode of action. Recent evidence in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), suggests that GA effects on NK cells and B cells may contribute to therapeutic efficacy. We review the mechanism of action of GA, with particular focus on recent data suggesting a role for regulatory B cells.

Burden of multiple sclerosis on direct, indirect costs and quality of life: National US estimates.

BACKGROUND MS imposes a significant burden on patients, caregivers, employers, and the healthcare system. OBJECTIVE To comprehensively evaluate the US MS burden using nationally representative data from the Medical Expenditure Panel Survey. METHODS We identified non-institutionalized patients aged ≥18 with MS (ICD-9 code 340) from 1998 to 2009 and compared them to individuals without an MS diagnosis (non-MS) during the interview year. The cohorts were compared using multivariate regression on direct costs, indirect costs (measured in terms of employment status, annual wages, and workdays missed), and health-related quality of life (HRQoL; measured using Short Form 12, SF-6 Dimensions, and quality-adjusted life years [QALYs]). RESULTS MS prevalence was 572,312 (95% CI: 397,004, 747,619). Annual direct costs were

Considerations on Discontinuing Natalizumab for the Treatment of Multiple Sclerosis

24,327 higher for the MS population (n=526) vs. the non-MS population (n=270,345) (95% CI:

Remyelination Therapy in Multiple Sclerosis

22,320,

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

26,333). MS patients had an adjusted 3.3-fold (95% CI: 2.4, 4.5) increase in the odds of not being employed vs. non-MS individuals and a 4.4-fold higher adjusted number of days in bed (95% CI 2.97, 6.45). On average, MS patients lost 10.04 QALYs vs. non-MS cohort. CONCLUSIONS MS was associated with higher healthcare costs across all components, reduced productivity due to unemployment and days spent in bed, and lower HRQoL.

Therapeutic options in multiple sclerosis Five new things

Considerations on Discontinuing Natalizumab for the Treatment of Multiple Sclerosis Joseph R. Berger, MD, Diego Centonze, MD, Giancarlo Comi, MD, Christian Confavreux, MD, Gary Cutter, PhD, Gavin Giovannoni, MD, Ralf Gold, MD, Hans-Peter Hartung, MD, Fred Lublin, MD, Augusto Miravalle, MD, Xavier Montalban, MD, Paul O’Connor, MD, Tomas Olsson, MD, PhD, Chris H. Polman, MD, Olaf Stuve, MD, PhD, Jerry S. Wolinsky, MD, and Tjalf Ziemssen, MD

Neurological complications following vaccinations.

Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath that surrounds axons and eventual neurodegeneration. Current treatments approved for the treatment of relapsing forms of MS target the aberrant immune response and successfully reduce the severity of attacks and frequency of relapses. Therapies are still needed that can repair damage particularly for the treatment of progressive forms of MS for which current therapies are relatively ineffective. Remyelination can restore neuronal function and prevent further neuronal loss and clinical disability. Recent advancements in our understanding of the molecular and cellular mechanisms regulating myelination, as well as the development of high-throughput screens to identify agents that enhance myelination, have lead to the identification of many potential remyelination therapies currently in preclinical and early clinical development. One problem that has plagued the development of treatments to promote remyelination is the difficulty in assessing remyelination in patients with current imaging techniques. Powerful new imaging technologies are making it easier to discern remyelination in patients, which is critical for the assessment of these new therapeutic strategies during clinical trials. This review will summarize what is currently known about remyelination failure in MS, strategies to overcome this failure, new therapeutic treatments in the pipeline for promoting remyelination in MS patients, and new imaging technologies for measuring remyelination in patients.

Maximally tolerated versus minimally effective dose: the case of rituximab in multiple sclerosis

BACKGROUND Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.