George J. Hutton

Multiple sclerosis risk after optic neuritis: Final optic neuritis treatment trial follow-up

OBJECTIVE To assess the risk of developing multiple sclerosis (MS) after optic neuritis and the factors predictive of high and low risk. DESIGN Subjects in the Optic Neuritis Treatment Trial, who were enrolled between July 1, 1988, and June 30, 1991, were followed up prospectively for 15 years, with the final examination in 2006. SETTING Neurologic and ophthalmologic examinations at 13 clinical sites. PARTICIPANTS Three hundred eighty-nine subjects with acute optic neuritis. MAIN OUTCOME MEASURES Development of MS and neurologic disability assessment. RESULTS The cumulative probability of developing MS by 15 years after onset of optic neuritis was 50% (95% confidence interval, 44%-56%) and strongly related to presence of lesions on a baseline non-contrast-enhanced magnetic resonance imaging (MRI) of the brain. Twenty-five percent of patients with no lesions on baseline brain MRI developed MS during follow-up compared with 72% of patients with 1 or more lesions. After 10 years, the risk of developing MS was very low for patients without baseline lesions but remained substantial for those with lesions. Among patients without lesions on MRI, baseline factors associated with a substantially lower risk for MS included male sex, optic disc swelling, and certain atypical features of optic neuritis. CONCLUSIONS The presence of brain MRI abnormalities at the time of an optic neuritis attack is a strong predictor of the 15-year risk of MS. In the absence of MRI-detected lesions, male sex, optic disc swelling, and atypical clinical features of optic neuritis are associated with a low likelihood of developing MS. This natural history information is important when considering prophylactic treatment for MS at the time of a first acute onset of optic neuritis.

Spectrum of pediatric neuromyelitis optica.

OBJECTIVE. Our goal was to describe the spectrum of clinical phenotypes, laboratory and imaging features, and treatment in pediatric patients with neuromyelitis optica. PATIENTS AND METHODS. The study consisted of a retrospective chart review of patients followed in a pediatric multiple sclerosis center with a diagnosis of neuromyelitis optica spectrum disorder. RESULTS. Nine patients with neuromyelitis optica spectrum disorders were included, all of whom were female. There were 4 black children, 2 Latin American children, 2 white children, and 1 child of mixed Latin American/white heritage. Median age at initial attack was 14 years (range: 1.9–16 years). Median disease duration was 4 years (range: 0.6–9 years). Tests for neuromyelitis optica immunoglobulin G were positive for 7 patients. Eight patients had transverse myelitis and optic neuritis, and 1 patient had longitudinally extensive transverse myelitis without optic neuritis but had a positive neuromyelitis optica immunoglobulin G antibody titer. Cerebral involvement on MRI was found in all subjects, 5 of whom were symptomatic with encephalopathy, seizures, hemiparesis, aphasia, vomiting, or hiccups. Immunosuppressive therapy reduced attack frequency and progression of disability. CONCLUSIONS. Pediatric neuromyelitis optica has a diverse clinical presentation and may be difficult to distinguish from multiple sclerosis in the early stages of the disease. The recognition of the broad spectrum of this disease to include signs and symptoms of brain involvement is aided by the availability of a serum biomarker: neuromyelitis optica immunoglobulin G. Early diagnosis and immunosuppresive treatment may help to slow the accumulation of severe disability.

High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS): A 3-Year Interim Report

IMPORTANCE Most patients with relapsing-remitting (RR) multiple sclerosis (MS) who receive approved disease-modifying therapies experience breakthrough disease and accumulate neurologic disability. High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic cell transplant (HCT) may, in contrast, induce sustained remissions in early MS. OBJECTIVE To evaluate the safety, efficacy, and durability of MS disease stabilization through 3 years after HDIT/HCT. DESIGN, SETTING, AND PARTICIPANTS Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) is an ongoing, multicenter, single-arm, phase 2 clinical trial of HDIT/HCT for patients with RRMS who experienced relapses with loss of neurologic function while receiving disease-modifying therapies during the 18 months before enrolling. Participants are evaluated through 5 years after HCT. This report is a prespecified, 3-year interim analysis of the trial. Thirty-six patients with RRMS from referral centers were screened; 25 were enrolled. INTERVENTIONS Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. MAIN OUTCOMES AND MEASURES The primary end point of HALT-MS is event-free survival defined as survival without death or disease activity from any one of the following outcomes: (1) confirmed loss of neurologic function, (2) clinical relapse, or (3) new lesions observed on magnetic resonance imaging. Toxic effects are reported using National Cancer Institute Common Terminology Criteria for Adverse Events. RESULTS Grafts were collected from 25 patients, and 24 of these individuals received HDIT/HCT. The median follow-up period was 186 weeks (interquartile range, 176-250) weeks). Overall event-free survival was 78.4% (90% CI, 60.1%-89.0%) at 3 years. Progression-free survival and clinical relapse-free survival were 90.9% (90% CI, 73.7%-97.1%) and 86.3% (90% CI, 68.1%-94.5%), respectively, at 3 years. Adverse events were consistent with expected toxic effects associated with HDIT/HCT, and no acute treatment-related neurologic adverse events were observed. Improvements were noted in neurologic disability, quality-of-life, and functional scores. CONCLUSIONS AND RELEVANCE At 3 years, HDIT/HCT without maintenance therapy was effective for inducing sustained remission of active RRMS and was associated with improvements in neurologic function. Treatment was associated with few serious early complications or unexpected adverse events.

Gene expression profiling of relevant biomarkers for treatment evaluation in multiple sclerosis

Multiple sclerosis (MS) is thought to correlate with an array of clinically relevant biomarkers produced during inflammatory process. In this study, a novel gene expression profiling technology was developed and characterized to quantitatively measure the expression profiles of 34 genes selected based on their role in inflammation and their susceptibility to regulation by current MS treatment agents, beta-interferon (IFN) and glatiramer acetate (GA). Potential clinical applications of the technology were evaluated by in vitro and ex vivo analyses in peripheral blood mononuclear cells (PBMC) obtained from MS patients and controls. Interferon-inducible genes were universally up-regulated after in vitro treatment with beta-IFN while the expression of other selected genes encoding cytokines and molecules related to T cell trafficking, activation and apoptosis was variably affected. Beta-IFN and GA exhibited distinctive and characteristic regulatory effects on the expression of the selected genes. Similar regulatory properties of beta-IFN and GA were seen by ex vivo analysis of PBMC specimens in a self-paired study by comparing specific changes induced by beta-IFN or GA treatment in the same patients as well as in a group study by measuring specific profiles in treatment groups compared with an untreated group. Furthermore, the technology served as a simple and sensitive assay for detection of beta-IFN neutralizing antibody based on the blocking effect of serum antibodies on the known regulatory properties of beta-IFN on PBMC. The findings provide important information on the immunoregulatory properties of beta-IFN and GA and support potential clinical applications of this technology in detection of neutralizing antibody (NAB) and evaluation of treatment responses in MS patients.

Human herpesvirus-6 encephalitis following allogeneic hematopoietic stem cell transplantation

Immunosuppressive monoclonal antibodies directed to immune system cells may reduce rejection and graft versus host disease (GvHD) after allogeneic stem cell transplantation (SCT), but can increase the risks of viral infection. Here, we report human herpes virus-6 (HHV-6) encephalitis despite antiviral prophylaxis in 5 of 43 (11.6%) patients receiving alemtuzumab supported conditioning. Encephalitis occurred at 41–103 days (median 60 days) presenting with confusion in all patients, combined with amnesia (n=3) or seizures (n=2). MRI revealed non-specific white matter changes in two and a non-enhancing medial temporal lobe lesion in three patients. Cerebrospinal fluid (CSF) PCR amplification for HHV-6 was positive in all five patients, (600–2 25 000 (median 4700) copies/ml CSF), while analysis of peripheral blood revealed 100–22 500 (median 1200) viral copies/ml plasma. CSF protein was elevated in four patients, with minimal CSF pleocytosis. Intravenous foscarnet produced neurological improvement at 8–13 (median 11) days and negative plasma PCR at 30–66 (median 50) days. Four patients had complete neurological recovery, but one patient with persistent viral DNA in the CSF succumbed to progressive encephalopathy. Given this high incidence of HHV-6 and the possibility of successful outcome with prompt treatment, a high index of suspicion of this disorder is required in recipients of monoclonal antibody supported allografts.

Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS

Objective: To assess the safety, tolerability, and efficacy of interferon beta-1a (IFNβ-1a) combined with methotrexate (MTX), IV methylprednisolone (IVMP), or both in patients with relapsing-remitting multiple sclerosis (RRMS) with continued disease activity on IFNβ-1a monotherapy. Methods: Eligibility criteria included RRMS, Expanded Disability Status Scale score 0–5.5, and ≥1 relapse or gadolinium-enhancing MRI lesion in the prior year on IFNβ-1a monotherapy. Participants continued weekly IFNβ-1a 30 μg IM and were randomized in a 2 × 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without bimonthly IVMP 1,000 mg/day for 3 days. The primary endpoint was new or enlarged T2 lesion number at month 12 vs baseline. The study was industry-supported, collaboratively designed, and governed by an investigator Steering Committee with independent Advisory and Data Safety Monitoring committees. Study operations, MRI analyses, and aggregated data were managed by an academic coordinating center. Results: The 313 participants had clinical and MRI characteristics typical of RRMS. Combinations of IFNβ-1a with MTX or IVMP were generally safe and well tolerated. Although trends suggesting modest benefit were seen for some outcomes for IVMP, the results did not demonstrate significant benefit for either adjunctive therapy. The data suggested IVMP reduced anti-IFNβ neutralizing antibody titers. Conclusions: This trial did not demonstrate benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis. ACT = Avonex Combination Trial; BPF = brain parenchymal fraction; DEXA= dual energy X-ray absorptiometry; EDSS = Expanded Disability Status Scale; GdE = gadolinium-enhancing; IFNβ-1a = interferon beta-1a; IVMP = IV methylprednisolone; MSFC = MS Functional Composite; MTX = methotrexate; N/E = new or enlarged; NAb = neutralizing antibody; OR = odds ratio; RRMS = relapsing-remitting multiple sclerosis; SENTINEL = Safety and Efficacy of Natalizumab in Combination with Interferon β-1a in Patients with Relapsing-Remitting MS.

IFN-β induces the proliferation of CD4+CD25+Foxp3+ regulatory T cells through upregulation of GITRL on dendritic cells in the treatment of multiple sclerosis

IFN-β is a major disease-modifying agent used for the treatment of multiple sclerosis (MS). Its mechanisms are complex and it has broad immunomodulatory effects on many types of immune cells. It was observed clinically that the quantity of CD4(+)CD25(+)Foxp3(+) regulatory T cells increases in some MS patients treated with IFN-β. In this study, we show that IFNAR engagement by IFN-β expands naturally occurring CD4(+)CD25(+)Foxp3(+) regulatory T cell population through the modulation of dendritic cells (DCs). IFN-β has no effect on the conversion of CD4(+)CD25(-) T cells to adaptive Treg cells. The IFN-β-induced upregulation of GITRL on DC and downregulation of CTLA-4 on Treg cell work together to facilitate the proliferation of anergic Treg cells. In MS patients treated with Avonex or Rebif (IFN-β), it was found that GITRL expression is markedly upregulated on peripheral CD14(+) cells. Our findings help the better understanding of the complex effects of IFN-β in the treatment of MS.

A comparison of the mechanisms of action of interferon beta and glatiramer acetate in the treatment of multiple sclerosis

BACKGROUND The development of immunomodulatory agents has represented a major advance in the treatment of multiple sclerosis (MS). To date, immunomodulatory agents approved for the treatment of relapsing MS in the United States include 3 forms of recombinant interferon (IFN) beta (2 formulations of IFN beta-1a and 1 of IFN beta-1b) and synthetic glatiramer acetate (GA). Recognition of how these agents work to regulate the immune system may lead to a better understanding of disease mechanisms, as well as to development of more effective therapies or combinations of therapy. OBJECTIVE This article reviews the potential mechanisms of action of IFN beta products and GA in the context of their regulatory effects on autoimmune components that may be of importance in MS. METHODS MEDLINE and Current Contents/Clinical Medicine were searched for articles published in English from 1993 to the present using the search terms interferon beta, glatiramer acetate, and multiple sclerosis. RESULTS IFN beta products affect the disease process in MS through multiple potential mechanisms of action, including antiviral, antiproliferative, and anti-inflammatory effects. The mechanisms of action of GA are less clear, but may involve immune regulation induced by a gradual shift of T-cell phenotype from proinflammatory (type 1 T-helper cells) to anti-inflammatory (type 2 T-helper cells) and interference with antigen presentation. CONCLUSION Understanding the mechanisms of action of IFN beta products and GA provides important insights into the disease processes involved in MS.

Functional Brain Network Changes Associated with Maintenance of Cognitive Function in Multiple Sclerosis

In multiple sclerosis (MS) functional changes in connectivity due to cortical reorganization could lead to cognitive impairment (CI), or reflect a re-adjustment to reduce the clinical effects of widespread tissue damage. Such alterations in connectivity could result in changes in neural activation as assayed by executive function tasks. We examined cognitive function in MS patients with mild to moderate CI and age-matched controls. We evaluated brain activity using functional magnetic resonance imaging (fMRI) during the successful performance of the Wisconsin card sorting (WCS) task by MS patients, showing compensatory maintenance of normal function, as measured by response latency and error rate. To assess changes in functional connectivity throughout the brain, we performed a global functional brain network analysis by computing voxel-by-voxel correlations on the fMRI time series data and carrying out a hierarchical cluster analysis. We found that during the WCS task there is a significant reduction in the number of smaller size brain functional networks, and a change in the brain areas representing the nodes of these networks in MS patients compared to age-matched controls. There is also a concomitant increase in the strength of functional connections between brain loci separated at intermediate-scale distances in these patients. These functional alterations might reflect compensatory neuroplastic reorganization underlying maintenance of relatively normal cognitive function in the face of white matter lesions and cortical atrophy produced by MS.

Regulation of differentiation and functional properties of monocytes and monocyte-derived dendritic cells by interferon beta in multiple sclerosis

Interferon beta (IFN beta) has complex immune regulatory properties that contribute to its treatment effect on multiple sclerosis (MS). In this study, we investigated the role of IFN beta in differentiation and functional properties of monocytes and monocyte-derived dendritic cells that are critical to the inflammatory process in MS. The results revealed that IFN beta inhibited intracellular production of interleukin (IL)-1b (PB/0.01) in both monocytes exposed toin vitro treatment of IFN beta and monocytes analysedex vivo from MS patients treated with IFN beta. IFN beta was shown to modulate differentiation of monocytes into dendritic cells in the presence of IL-4 and GM-CSF, which resulted in a delayed differentiation process. Furthermore, it characteristically altered the phenotypic features of differentiated dendritic cells by inhibiting the expression of CD1a, CD11b, CD11c, CD123 and CD209 while upregulating costimulatory molecules, such as CD86. The selective regulatory properties of IFN beta appeared to render the function of differentiated dendritic cells to produce an increased amount (PB/0.01) while their ability to secrete proinflammatory IL-12 and TGF beta was significantly reduced. The observed collective effects of IFN beta seemed to correlate with Th2 immune deviation. The study has provided new insights into the regulatory mechanisms of IFN beta in the treatment of MS.