Jeffrey Dunn

Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis

Forty relapsing multiple sclerosis patients with 1–15 gadolinium (Gd)-enhancing lesions on screening brain magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) scores 0–6.5 were randomized to receive short-term induction therapy with mitoxantrone (three monthly 12 mg/m2 infusions) followed by 12 months of daily glatiramer acetate (GA) therapy 20 mg/day subcutaneously for a total of 15 months (M-GA, n = 21) or daily GA 20 mg/day for 15 months (GA, n = 19). MRI scans were performed at months 6, 9, 12 and 15. The primary measure of outcome was the incidence of adverse events; secondary measures included number of Gd-enhanced lesions, confirmed relapses and EDSS changes. Except age, baseline demographic characteristics were well matched in both treatment arms. Both treatments were safe and well tolerated. M-GA induction produced an 89% greater reduction (relative risk (RR) = 0.11, 95% confidence interval (CI): 0.04–0.36, p = 0.0001) in the number of Gd-enhancing lesions at months 6 and 9 and a 70% reduction (RR = 0.30, 95% CI: 0.11–0.86, p = 0.0147) at months 12 and 15 versus GA alone. Mean relapse rates were 0.16 and 0.32 in the M-GA and GA groups, respectively. Short-term immunosuppression with mitoxantrone followed by daily GA for up to 15 months was found to be safe and effective, with an early and sustained decrease in MRI disease activity.

Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis

Abstract Background: Multiple sclerosis (MS) can cause progressive walking impairment that contributes to disability, loss of independence, and reduced quality of life. Dalfampridine (4-aminopyridine), a voltage-dependent potassium channel blocker, has been shown to improve walking in patients with MS, as demonstrated by an increase in walking speed. Objective: To summarize knowledge about the mechanism of action of dalfampridine in the context of clinical evidence of walking improvement in MS patients. Methods: Although this was not a systematic review, which is the primary limitation of this study, searches of PubMed were performed using relevant search terms to identify studies that examined the mechanism of action related to MS and its effects in patients with MS in clinical trials. Results: Voltage-gated potassium channels represent a family of related proteins that span cell membranes, open and close in response to changes in the transmembrane potential, and help regulate ionic potassium currents. Action potential conduction deficits in demyelinated axons result in part from the exposure after demyelination of the paranodal and internodal potassium channels that are distributed in the axonal membrane. This exposure leads to abnormal currents across the axonal membrane that can slow action potential conduction, result in conduction failure, or affect the axons capacity for repetitive discharge. While dalfampridine is a broad-spectrum blocker of voltage-dependent potassium channels at millimolar concentrations, studies have shown improvement in action potential conduction in demyelinated axons at concentrations as low as 1 μM, and therapeutic plasma concentrations (associated with improved walking) are in the range of 0.25 µM. However, no specific potassium channel subtype has yet been characterized with significant sensitivity to dalfampridine in this range, and the effects of the drug at this low concentration appear to be quite selective. Improved conduction translates into clinical benefit as measured by objectively and subjectively assessed walking relative to placebo. Such improvements were observed in approximately one third of patients treated with an extended-release formulation of dalfampridine in clinical trials. These patients who responded to dalfampridine had an average increase in walking speed of approximately 25%, and greater improvements than nonresponders on a self-reported subjective measure of walking. Conclusions: The extended-release formulation of dalfampridine has been shown in clinical trials to improve walking speed in approximately one third of MS patients with ambulatory impairment. The putative mechanism of action of dalfampridine is restoration of action potential conduction via blockade of an as yet uncharacterized subset of potassium channels in demyelinated axons.

Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein.

Background: The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-β treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis (EAE) induced with Th17 cells is exacerbated by IFN-β, in contrast to disease induced with Th1 where treatment attenuated symptoms. Objective: This study demonstrates the similarities between NMO and Th17 EAE and how neutrophils mediate pathology in Th17 disease. Methods: Levels of blood biomarkers in NMO were assessed by Luminex and ELISA. Effects of IFN-β on neutrophils were assessed by culture assays and immunofluorescence. EAE was induced by transfer of myelin-specific Th1 or Th17 cells and treated with Sivelestat sodium hydrate, a neutrophil elastase inhibitor. Results: We show Th17 cytokines, granulocyte chemokines, type 1 interferon and neutrophil elastase are elevated in patients with definitive NMO. In culture, we find that IFN-β stimulates neutrophils to release neutrophil elastase. In Th17 EAE, we demonstrate neutrophilic infiltration in the optic nerve and spinal cord which was not present in Th1 EAE. Blockade of neutrophil elastase with Sivelestat had efficacy in Th17 EAE but not Th1 EAE. Conclusions: The similarities between Th17 EAE and NMO indicate that this model represents several aspects of NMO. Neutrophils are critical in the pathologies of both Th17-EAE and NMO, and therefore blockade of neutrophil elastase is a promising target in treating NMO.

Intracerebral Bacillary Angiomatosis in a Patient Infected with Human Immunodeficiency Virus

Excerpt Bacillary angiomatosis is a recently described illness that results from infection with a novel, rickettsia-like, gram-negative bacillus (1, 2). This disorder occurs predominantly in patien...

Impact of mobility impairment on the burden of caregiving in individuals with multiple sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated neurologic disease that typically strikes young adults during their most productive years, and is associated with a wide range of functional deficits and progressive disability. Loss of mobility is among the most disabling effects of MS, adversely affecting multiple outcomes, including independence, employment and quality of life. Relative to other common diseases, MS is associated with a disproportionately high socioeconomic burden. Informal and unpaid caregivers, such as family and friends, play a vital, sustained and often difficult role in supporting the ability of MS patients to live and function at home. However, there are few data characterizing caregiver burden in MS. This review was conducted to examine the need and impact of caregiving for patients with MS, focusing on the contribution of mobility impairment to loss of patient independence.

Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS

BackgroundGlatiramer acetate (GA) therapy following brief, low-dose induction with mitoxantrone was safe and more effective than GA alone in suppressing inflammatory disease activity, as determined by a significant reduction in gadolinium (Gd)- enhancing MRI lesions, in a 15- month, randomized, single-blind study of relapsing-remitting multiple sclerosis (RRMS) patients.ObjectiveTo determine whether effects on MRI markers of disease burden and tissue damage support and extend data on the benefits of mitoxantrone induction therapy before initiation of long-term GA therapy.Design/methods40 RRMS patients, aged 18 to 55 years, with 1–15 Gd-enhancing lesions on screening MRI and EDSS score 0–6.5 were randomized to receive GA (20 mg/d SC), starting 2 weeks after the last of 3 monthly mitoxantrone infusions (36 mg/m2 total; n = 21), or to GA alone (20 mg/d SC; n = 19), for a total of 15 months. MRIs were obtained at baseline and months 6, 9, 12, and 15.ResultsAt baseline, mean (± SD) age was 37.2 ± 9.7 years; disease duration, 3.5 ± 4.8 years; EDSS score, 2.3 ± 1.1; and number of Gd-enhancing lesions, 3.75 ± 3.95. Reductions in Gd-enhancing lesions (RR = 0.30, 95 % CI, 0.11–0.86, p = 0.0147) and relapse activity favoring mitoxantrone- GA were accompanied by significant differences in changes in T2w lesion volume (p = 0.0139), T1w hypointense lesion volume (p = 0.0303), and proportion of Gdenhancing lesions that evolved into black holes (p = 0.0023) compared with GA alone.ConclusionsLongterm continuous GA after brief, low-dose mitoxantrone induction is safe and more effective than GA alone. A trend toward decreased clinical disease activity was accompanied by major effects on MRI measures of disease burden and severe tissue injury.

IFN-β Treatment Requires B Cells for Efficacy in Neuroautoimmunity

IFN-β remains the most widely prescribed treatment for relapsing remitting multiple sclerosis. Despite widespread use of IFN-β, the therapeutic mechanism is still partially understood. Particularly, the clinical relevance of increased B cell activity during IFN-β treatment is unclear. In this article, we show that IFN-β pushes some B cells into a transitional, regulatory population that is a critical mechanism for therapy. IFN-β treatment increases the absolute number of regulatory CD19+CD24++CD38++ transitional B cells in peripheral blood relative to treatment-naive and Copaxone-treated patients. In addition, we found that transitional B cells from both healthy controls and IFN-β–treated MS patients are potent producers of IL-10, and that the capability of IFN-β to induce IL-10 is amplified when B cells are stimulated. Similar changes are seen in mice with experimental autoimmune encephalomyelitis. IFN-β treatment increases transitional and regulatory B cell populations, as well as IL-10 secretion in the spleen. Furthermore, we found that IFN-β increases autoantibody production, implicating humoral immune activation in B cell regulatory responses. Finally, we demonstrate that IFN-β therapy requires immune-regulatory B cells by showing that B cell–deficient mice do not benefit clinically or histopathologically from IFN-β treatment. These results have significant implications for the diagnosis and treatment of relapsing remitting multiple sclerosis.

Cytomegalovirus infection with MRI signal abnormalities affecting the optic nerves, optic chiasm, and optic tracts.

A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.

Infectious Complications of Multiple Sclerosis Therapies: Implications for Screening, Prophylaxis, and Management

Abstract Multiple sclerosis therapies include interferons, glatiramer, and multiple immunosuppressive drugs. Discerning infectious risks of immunosuppressive drugs requires understanding their mechanisms of action and analyzing interventional studies and postmarketing observational data. Though identical immunosuppressive therapies are sometimes used in non-neurologic conditions, infectious risks may differ in this population. Screening for and treatment of latent tuberculosis (TB) infection should be prioritized for patients receiving alemtuzumab; ocrelizumab is likely not associated with an increased risk of TB. Hepatitis B virus (HBV) reactivation can be devastating for patients treated with ocrelizumab and alemtuzumab, whereas the small molecule oral agents do not likely pose substantial risk of HBV. Progressive multifocal leukoencephalopathy is a particular concern with natalizumab. Alemtuzumab, and possibly natalizumab and fingolimod, risks herpes virus reactivation and may warrant prophylaxis. Unusual opportunistic infections have been described. Vaccination is an important tool in preventing infections, though vaccine timing and contraindications can be complex.

Disease-modifying therapies for nonrelapsing multiple sclerosis Absence of evidence does not constitute evidence of absence

The lack of clinical trial data demonstrating efficacy of disease-modifying treatments (DMTs) for nonrelapsing forms of multiple sclerosis (MS) does not prove that DMTs are ineffective for nonrelapsing MS. It has been argued that DMTs have met primary endpoints in relapsing MS, but not in nonrelapsing forms of the disease. This does not prove that such treatments are ineffective for nonrelapsing phenotypes. It could mean that clinical trial endpoints are ineffective in identifying true differences between treatment and placebo arms, or do not properly account for individual variation within clinical trial cohorts.